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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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APC-Associated Polyposis Conditions

, MS and , MD.

Author Information
, MS
Huntsman Cancer Institute
Salt Lake City, Utah
, MD
Huntsman Cancer Institute
Salt Lake City, Utah

Initial Posting: ; Last Update: March 27, 2014.

Summary

Disease characteristics. APC-associated polyposis conditions include: familial adenomatous polyposis (FAP), attenuated FAP, Gardner syndrome, and Turcot syndrome.

FAP is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop, beginning, on average, at age 16 years (range 7-36 years). By age 35 years, 95% of individuals with FAP have polyps; without colectomy, colon cancer is inevitable. The mean age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Extracolonic manifestations are variably present and include: polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers.

Attenuated FAP is characterized by a significant risk for colon cancer but fewer colonic polyps (average of 30), more proximally located polyps, and diagnosis of colon cancer at a later age; management may be substantially different.

Gardner syndrome is characterized by colonic polyposis typical of FAP together with osteomas and soft tissue tumors.

Turcot syndrome is the association of colonic polyposis and central nervous system (CNS) tumors. Differences in phenotype may relate to the location of the pathogenic variant within APC.

Diagnosis/testing. APC is the only gene in which pathogenic variants cause APC-associated polyposis conditions. The diagnosis relies primarily on clinical findings. Molecular genetic testing of APC detects pathogenic variants in up to 90% of individuals with typical FAP. Molecular genetic testing is most often used in the early diagnosis of at-risk family members, as well as in confirming the diagnosis of FAP or attenuated FAP in individuals with equivocal findings (e.g., <100 adenomatous polyps).

Management. Treatment of manifestations: Colectomy is advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have occurred. Nonsteroidal anti-inflammatory drugs (NSAIDs), especially sulindac, have caused regression of adenomas in FAP and decreased the number of polyps requiring ablation in the remaining rectum of persons with a subtotal colectomy. Endoscopic or surgical removal of duodenal adenomas is considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms. Osteomas may be removed for cosmetic reasons. Desmoid tumors may be surgically excised or treated with NSAIDs, anti-estrogens, cytotoxic chemotherapy, or radiation.

Surveillance: Screening for hepatoblastoma by liver ultrasound and measurement of serum alpha-fetoprotein concentration (until age 5 years); sigmoidoscopy or colonoscopy beginning at age ten to 12 years; annual colonoscopy once polyps are detected until colectomy; esophagogastroduodenoscopy by age 25 years or prior to colon surgery; small bowel x-ray or CT when duodenal adenomas are detected; and regular physical examinations including thyroid palpation and possibly thyroid ultrasound imaging.

Evaluation of relatives at risk: Molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant.

Genetic counseling. APC-associated polyposis conditions are inherited in an autosomal dominant manner. Approximately 75%-80% of individuals with APC-associated polyposis conditions have an affected parent. Offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant in APC. Prenatal testing and preimplantation genetic diagnosis may be an option if a pathogenic variant has been identified in an affected family member.

GeneReview Scope

APC-Associated Polyposis Conditions: Included Disorders
  • Familial adenomatous polyposis
  • Gardner syndrome
  • Turcot syndrome
  • Attenuated FAP

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

The APC-associated polyposis conditions include: (1) the overlapping, often indistinguishable phenotypes of familial adenomatous polyposis (FAP), Gardner syndrome, and Turcot syndrome; and (2) attenuated FAP, which has a lower colonic polyp burden and lower cancer risk:

Familial adenomatous polyposis (FAP) is diagnosed clinically in an individual with one of the following:

  • At least 100 colorectal adenomatous polyps
    Note: (1) The diagnosis of FAP is generally considered in individuals with polyposis occurring before age 40 years. (2) The presence of 100 or more colorectal polyps is not specific to FAP; genetic testing of APC may help distinguish FAP from MUTYH-associated polyposis (MAP) (see Differential Diagnosis) or colonic polyposis conditions of unknown etiology.
  • Fewer than 100 adenomatous polyps and a relative with FAP

Gardner syndrome is the association of colonic adenomatous polyposis, osteomas, and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors) [Gardner & Richards 1953].

Turcot syndrome is the association of colonic adenomatous polyposis and CNS tumors, usually medulloblastoma.

Attenuated FAP is considered in an individual with one of the following:

  • Ten to 99 colonic adenomatous polyps
    Note: Individuals with 100 or more polyps occurring at “advanced” ages (35 to 40 years or older) may be found to have attenuated FAP.
  • A personal history of colorectal cancer before age 60 years and a family history of multiple adenomatous polyps

Currently, there is no consensus regarding the exact diagnostic criteria to be used for attenuated FAP. Nielsen et al [2007b] proposed the following diagnostic criteria for attenuated FAP:

  • No family member with more than 100 polyps before age 30 years

    AND
  • At least two individuals with 10 to 99 adenomas diagnosed after age 30 years

    OR
  • One individual with 10 to 99 adenomas diagnosed after age 30 years and a first-degree relative with colorectal cancer with a few adenomas

Note: (1) This proposed definition takes into account the variability in colonic phenotype seen in attenuated FAP (i.e., some individuals may have ≥100 polyps at a later age, although most have <100 polyps) [Burt et al 2004]. (2) One limitation in the proposed criteria is that they do not take into account APC genetic status: a significant proportion of persons with polyposis who do not have an identified APC pathogenic variant are found to have biallelic MUTYH pathogenic variants and therefore should be classified as having MUTYH-associated polyposis (see Differential Diagnosis).

Knudsen et al [2010] proposed the following diagnostic criteria for attenuated FAP:

  • Dominant mode of inheritance of colorectal adenomatosis

    AND
  • Fewer than 100 colorectal adenomas at age 25 years or older

Note: The criteria proposed by Knudsen and colleagues for attenuated FAP have several limitations: (1) they do not take into account APC genetic status; (2) they do not define how many polyps are needed for colorectal adenomatosis; (3) a dominant mode of inheritance may not be evident from the family history, given that 20%-25% of persons with an APC-associated polyposis condition represent simplex cases (i.e., a single occurrence in a family).

Variable features not included in the diagnostic criteria of an APC-associated polyposis condition but potentially helpful in establishing the clinical diagnosis include: gastric polyps, duodenal adenomatous polyps, osteomas, dental abnormalities (especially supernumerary teeth and/or odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors (specifically epidermoid cysts and fibromas), desmoid tumors, and associated cancers.

Molecular Genetic Testing

Gene. APC is the only gene in which pathogenic variants cause APC-associated polyposis conditions.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in APC-Associated Polyposis Conditions

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method 2
APCSequence analysis 3≤90% 4
Duplication/deletion analysis 5~8%-12% 6, 7

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. The likelihood of detecting an APC pathogenic variant is highly dependent on the severity of colonic polyposis and on the family history. Detection rates are higher in classic polyposis than in attenuated colonic phenotypes [Sieber et al 2002, Aretz et al 2005, Michils et al 2005, Aretz et al 2006] and higher in individuals with a family history of polyposis than in those without affected family members in the previous generation [Truta et al 2005, Aretz et al 2007, Hes et al 2007]. Fewer than 30% of individuals with attenuated phenotypes are expected to have an identifiable APC pathogenic variant [Lefevre et al 2006].

3. Full gene sequencing of all APC exons and intron-exon boundaries appears to be the most accurate clinical test available to detect APC pathogenic variants [Hegde et al 2014]. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. Most APC pathogenic variants are nonsense or frameshift and cause premature truncation of the APC protein. For issues to consider in interpretation of sequence analysis results, click here.

4. Approximately 20% of individuals with apparent de novo APC mutation (i.e. no family history of an affected individual) have somatic mosaicism [Hes et al 2007]. In individuals with somatic mosaicism, sequencing of APC in DNA extracted from peripheral blood lymphocytes may fail to detect pathogenic variants because of weak mutation signals [Aretz et al 2007, Hes et al 2007]. This may explain (in part) the lower pathogenic variant detection rate in simplex cases (i.e., a single occurrence in a family) than in persons with an affected parent.

5. Testing that identifies large (exonic or whole-gene) deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Large deletion/duplication testing should also include analysis of the regulatory regions (specifically promoter 1B) of APC. In addition, individuals suspicious for an APC-associated polyposis condition with no deleterious APC mutation found, should be evaluated for promoter 1B deletions if these mutations were not analyzed in the initial testing [Rohlin et al 2011].

6. Approximately 8%-12% of individuals with an APC-associated polyposis condition and 100 or more polyps have a partial or whole APC deletion [Sieber et al 2002, Bunyan et al 2004, Aretz et al 2005, Michils et al 2005]. In one study, 19 (6%) of 296 individuals with ten or more adenomatous polyps who had no pathogenic variants in MUTYH (see Differential Diagnosis) or APC using sequencing, protein truncation testing, and denaturing gradient gel electrophoresis (a type of mutation scanning) had a large APC deletion detected by MLPA [Nielsen et al 2007b].

7. Interstitial deletions of chromosome 5q that include APC have been identified on routine chromosome analysis in several individuals with colonic polyposis and intellectual disability [Heald et al 2007]. In at least one individual, array comparative genomic hybridization (array CGH) detected a deletion that was not visible on routine cytogenetic studies [Heald et al 2007].

Linkage analysis. When no pathogenic variant is identified in an affected individual, linkage analysis can be considered in families with more than one affected family member belonging to different generations. Linkage studies are based on an accurate clinical diagnosis of an APC-associated polyposis condition in the affected family members and accurate understanding of genetic relationships in the family. Linkage analysis is dependent on the availability and willingness of family members to be tested. The markers used for linkage analysis of APC-associated polyposis conditions are highly informative and very tightly linked to the APC locus; thus, they can be used with greater than 98% accuracy in more than 95% of families with an APC-associated polyposis condition [Petersen et al 1991, Burt et al 1992]. Linkage testing is not possible for families with a single affected individual, a situation that often occurs when an individual has de novo gene mutation and no affected offspring.

Note: Protein truncation testing, which has a sensitivity of 70-90%, has largely been replaced by more sensitive sequencing techniques discussed above [Hegde et al 2014]. However, some laboratories continue to use protein truncation testing [Hegde et al 2014].

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Aretz et al 2011 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband. In individuals meeting the diagnostic criteria for FAP or individuals suspected of having an APC-associated polyposis condition, molecular genetic testing should be considered.

Sequential single gene testing. One strategy for molecular diagnosis of a proband suspected of having APC-associated polyposis conditions is sequential single gene testing.

  • Sequence analysis and duplication/deletion analysis of APC should be considered first.
  • Molecular genetic testing of MUTYH (see Differential Diagnosis) can be considered next if no APC pathogenic variant is found.

Concurrent testing. Another strategy is to perform concurrent genetic testing of two or more genes known to be associated with colon cancer predisposition.

  • Targeted concurrent testing. Concurrent molecular genetic testing for both APC and MUTYH may be considered. These two genes may also be represented together on a multi-gene panel (see following).
  • Multi-gene panel. A more recent strategy for molecular diagnosis of a proband suspected of having APC-associated polyposis conditions is use of a multi-gene panel. Multi-gene panels can be used for the simultaneous analysis of some or all of the genes known to be associated with intestinal polyposis conditions. These panels vary by methods used and genes included.

Note: Cytogenetic analysis and/or array CGH may be pursued when adenomatous polyposis is accompanied by developmental delay. Array CGH has been used to determine if APC is within cytogenetically visible chromosomal deletions that are close to APC [Wallerstein et al 2007].

Clinical Description

Natural History

APC-associated polyposis conditions include classic FAP, the overlapping phenotypes Gardner syndrome and Turcot syndrome, and attenuated FAP.

Classic FAP

Colorectal adenomatous polyps begin to appear, on average, at age 16 years (range 7-36 years) [Petersen et al 1991]. By age 35 years, 95% of individuals with classic FAP have polyps. Once they appear, the polyps rapidly increase in number; when colonic expression is fully developed, hundreds to thousands of colonic adenomatous polyps are typically observed. Without colectomy, colon cancer is inevitable. The average age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Seven percent of untreated individuals with FAP develop colon cancer by age 21 years, 87% by 45 years, and 93% by 50 years [Bussey 1975]. Although rare, asymptomatic individuals in their 50s have been reported [Evans et al 1993]. Inter- and intrafamilial phenotypic variability are common [Giardiello et al 1994, Rozen et al 1999].

Other Features Variably Present in FAP

Table 2. Lifetime Risk for Extracolonic Cancer in FAP

SiteType of CancerLifetime Risk for Cancer
Small bowel: duodenum or periampullaCarcinoma4%-12%
Small bowel: distal to the duodenumRare
PancreasAdenocarcinoma~1%
ThyroidPapillary thyroid carcinoma1%-12%
CNSUsually medulloblastoma<1%
LiverHepatoblastoma1.6%
Bile ductsAdenocarcinomaLow, but increased
StomachAdenocarcinoma<1% in Western cultures

Small-bowel polyps and cancer. Adenomatous polyps of the duodenum, observed in 50%-90% of individuals with FAP, are commonly found in the second and third portions of the duodenum [Kadmon et al 2001] and less frequently in the distal small bowel [Wallace & Phillips 1998]. A classification system for duodenal polyps, based on number and size of polyps, histology, and degree of dysplasia, has been developed [Spigelman et al 1989]. No clear association between the number of colonic polyps and the number of upper gastrointestinal polyps has been identified [Kadmon et al 2001].

Adenomatous polyps of the periampullary region (including the duodenal papilla and ampulla of Vater) are seen in at least 50% of individuals with classic FAP. Polyps in this area can cause obstruction of the pancreatic duct resulting in pancreatitis or biliary obstruction, both of which occur at increased frequency in FAP. These polyps are often small and require a side-viewing endoscope for visualization. Some theorize that pancreaticobiliary secretions (e.g., bile) affect the development of adenomas [Wallace & Phillips 1998], and may account for the observed increased risk for malignancy of polyps in the periampullary region [Kadmon et al 2001].

Duodenal adenocarcinoma occurs most commonly in the periampullary area. It has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years [Wallace & Phillips 1998, Kadmon et al 2001]. The lifetime risk for small bowel malignancy is 4%-12%; the majority occurs in the duodenum.

Small-bowel cancer distal to the duodenum occurs but is rare. Ruys et al [2010] identified only 17 cases of jejunal carcinoma and three cases of ilieal carcinoma in individuals with FAP reported in the literature [Ruys et al 2010].

Pancreatic cancer. Although limited data exist, one study of 197 families with FAP revealed a relative risk for pancreatic cancer of 4.5 in individuals with FAP and their at-risk relatives compared to the general population risk. The lifetime pancreatic cancer risk to age 80 in individuals with FAP was estimated to be 1% [Giardiello et al 1993].

Thyroid cancer and benign thyroid disease. There is a high degree of variability in the reported frequency of thyroid cancer in individuals with FAP. The incidence of thyroid cancer in retrospective series of individuals with FAP is 0.4% to 6.1% [Steinhagen et al 2012], whereas prospective ultrasound screening studies have found a prevalence of 2.6% to 12% [Herraiz et al 2007, Jarrar et al 2011]. Papillary histology predominates and may have a cribriform pattern [Jarrar et al 2011, Steinhagen et al 2012].

Data on the rate of benign thyroid disease in individuals with FAP are limited. In one retrospective study, 9.1% of individuals with FAP had benign thyroid disease (hypothyroidism, cysts, goiter, and/or thyroiditis) [Steinhagen et al 2012], whereas a prospective screening study found that 38% had benign thyroid nodules [Jarrar et al 2011]. Differences in sample size and study design (retrospective compared to prospective screening studies) likely contribute to the discrepancies in the rate of thyroid disease reported among studies. Familial occurrence and a female preponderance have been observed.

CNS. See Turcot syndrome.

Hepatoblastoma. The risk for hepatoblastoma in FAP is 750 to 7500 times higher than in the general population, although the absolute risk is estimated at less than 2% [Aretz et al 2007]. The majority of hepatoblastomas occur prior to age three years [Aretz et al 2007].

Gastric polyps and cancer. Gastric polyps can be either fundic gland or adenomatous [Bülow et al 1995]:

  • Gastric fundic gland polyps (hamartomatous tumors located in the fundus and body of the stomach) occur in approximately half of individuals with FAP [Offerhaus et al 1999]. For a complete review of gastric fundic gland polyps and their relationship to FAP and attenuated FAP, see Burt [2003].
  • Adenomatous polyps, the second most prevalent gastric lesion in individuals with FAP [Bülow et al 1995, Wallace & Phillips 1998], are usually confined to the gastric antrum [Offerhaus et al 1999].

The risk for gastric cancer in individuals with FAP living in Western cultures is low, although it has been reported [Offerhaus et al 1999, Garrean et al 2008]. The rates of gastric cancer in persons of Japanese and Korean heritage with FAP may be tenfold higher than the general population [Garrean et al 2008]. Gastric adenocarcinoma is believed to arise most often from adenomas but may also develop from fundic gland polyps [Zwick et al 1997, Hofgartner et al 1999, Attard et al 2001].

Extraintestinal Manifestations

Osteomas are bony growths found most commonly on the skull and mandible; however, they may occur in any bone of the body. Osteomas do not usually cause clinical problems and do not become malignant; they may appear in children prior to the development of colonic polyps.

Dental abnormalities. Unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts (an odontogenic cyst associated with the crown of an unerupted tooth), and odontomas have been reported in approximately 17% of individuals with FAP compared to 1%-2% of the general population [Brett et al 1994].

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) refers to discrete, flat, pigmented lesions of the retina that are not age dependent and do not cause clinical problems. Visualization of CHRPE may require examination of the ocular fundus with an indirect ophthalmoscope through a dilated pupil. Observation of multiple or bilateral CHRPE may be an indication that an at-risk family member has inherited FAP, whereas isolated lesions may be seen in the general population [Chen et al 2006].

Benign cutaneous lesions include epidermoid cysts and fibromas that may be found on any part of the body, including the face. They are mainly of cosmetic concern, as they do not appear to have malignant potential. Multiple pilomatricomas, although rare, have also been reported [Pujol et al 1995].

Desmoid tumors develop in approximately 10%-30% of individuals with FAP [Nieuwenhuis et al 2011b, Sinha et al 2011]. The risk for desmoid tumors in individuals with FAP is more than 800 times the risk in the general population [Nieuwenhuis et al 2011a]. At least 7.5% of desmoid type fibromatoses are found in people with FAP [Nieuwenhuis et al 2011a]. These poorly understood, benign fibrous tumors are clonal proliferations of myofibroblasts that are locally invasive but do not metastasize [Clark et al 1999]. A pathologically distinct fibromatous lesion called a Gardner-associated fibroma (GAF) is hypothesized to be a precursor lesion [Wehrli et al 2001].

The incidence of desmoid tumors in FAP is highest in the second and third decades of life, with 80% occurring by age 40 [Sinha et al 2011]. Approximately 65% of desmoid tumors in individuals with FAP occur within the abdomen or in the abdominal wall [Sinha et al 2011]. Desmoid tumors may compress abdominal organs or complicate abdominal surgery. About 5% of individuals with FAP experience morbidity and/or mortality from desmoid tumors, with the highest mortality rate reported for intra-abdominal tumors [Sinha et al 2011]. Abdominal desmoid tumors may occur spontaneously or following abdominal surgery [Bertario et al 2001]. The effect of pregnancy on desmoid tumor growth or development is unknown [Sinha et al 2011]. Independent predictors for desmoid tumor development include: an APC pathogenic variant 3' of codon 1399, family history of desmoid tumors, female gender, and previous abdominal surgery [Sinha et al 2011]. Positive family history of desmoid tumor was associated with the highest magnitude of risk; having a first-degree relative with a desmoid tumor was associated with a sevenfold increase in risk [Sinha et al 2011].

Desmoid tumors are best evaluated by CT scan [Clark & Phillips 1996] or MRI. A CT scoring system for desmoid tumors in FAP has been developed [Middleton et al 2003].

Adrenal masses are reportedly two to four times more prevalent in FAP than in the general population [Rekik et al 2010]. Adrenal masses are found in 1%-3% of the general population; a retrospective analysis identified adrenal masses in 7.4% of individuals with FAP [Marchesa et al 1997], and a prospective study of 107 individuals with FAP found 13% with an adrenal mass greater than or equal to 1.0 cm on abdominal CT scan [Smith et al 2000b]. Most of the masses are asymptomatic adenomas found incidentally, although functional lesions and carcinomas do occur [Marchesa et al 1997, Rekik et al 2010].

Pregnancy/hormone use. Limited information is available on the effect of pregnancy on females with FAP. In one study of 58 Danish women with FAP, the same frequency of fertility, pregnancy, and delivery was observed as in a control population [Johansen et al 1990]. A larger study of 162 women with FAP compared fertility rates before and after two types of colorectal surgery with a control population. Women with FAP who had not yet undergone surgery had the same fertility as a control population of normal women. Additionally, those women with FAP who had a colectomy with ileorectal anastomosis (IRA) had the same fertility as the control population. Fertility was significantly reduced in women with FAP who had a proctocolectomy with ileal pouch-anal anastomosis (IPAA) compared to the control population [Olsen et al 2003].

In another study, the prevalence of self-reported fertility problems was similar among individuals with FAP who had undergone IRA, IPAA, or proctocolectomy with ileostomy [Nieuwenhuis et al 2010]. However, those who had their first surgical procedure at a younger age had more postoperative fertility problems [Nieuwenhuis et al 2010].

Little evidence supports an association between desmoid tumor development or growth and pregnancy [Sinha et al 2011].

Women who have undergone colectomy are considered to be at the same risk for obstetric complications as any other woman who has had major abdominal surgery.

As anti-estrogen medications have been successfully used in the treatment of desmoid tumors, the development of desmoid tumors is thought to be affected by hormones important in pregnancy. However, one study has shown that women who had a previous pregnancy and developed a desmoid tumor had significantly fewer complications from the desmoid tumor than those who had never had a pregnancy [Church & McGannon 2000].

In a study of women with FAP at the time of their colectomy, no association was found between pregnancy history and colonic polyp severity; however, the proportion of parous women with severe duodenal disease was significantly higher than the proportion of nulliparous women [Suraweera et al 2007].

Some studies have suggested that female hormones protect against colorectal cancer development in the general population. In one woman, reduction in polyps after use of oral contraceptives was observed [Giardiello et al 2005].

Gardner Syndrome

Gardner syndrome is the association of colonic adenomatous polyposis of classic FAP with osteomas and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors) [Gardner & Richards 1953]. When these findings are prominent, many clinicians continue to use the term Gardner syndrome. However, they can occur in any individual with FAP, whether or not other extraintestinal findings are present.

Gardner syndrome was once thought to be a distinct clinical entity; however, it is now known that pathogenic variants in APC give rise to both classic FAP and Gardner syndrome. Other manifestations of FAP (e.g., upper gastrointestinal polyposis) are also found in Gardner syndrome. Some correlation exists between extraintestinal growths and pathogenic variant location in APC. See Genotype-Phenotype Correlations.

Turcot Syndrome

Turcot syndrome is the association of colonic polyposis or colorectal cancer and CNS tumors. The molecular basis of most Turcot syndrome is either mutation in APC associated with FAP or mutation in one of the mismatch repair genes associated with Lynch syndrome [Hamilton et al 1995]. The CNS tumors in individuals with APC pathogenic variants are typically medulloblastoma, whereas those with mismatch repair pathogenic variants are usually glioblastoma multiforme.

The risk for CNS tumors is substantially increased in persons with FAP, although the absolute risk is only approximately 1%. The existence of families with APC-associated polyposis conditions in which multiple individuals have CNS tumors raises the possibility of mutation specificity or modifying genes. Similar to Gardner syndrome, Turcot syndrome was once thought to be a distinct clinical entity, however, it is now assumed that all individuals with an APC pathogenic variant are at increased risk for brain tumors, albeit a relatively low lifetime risk.

Attenuated FAP

Attenuated FAP is characterized by fewer colonic polyps (average of 30) than classic FAP but a significant risk for colorectal cancer. Polyps tend to be found more proximally in the colon than in classic FAP.

The exact lifetime risk for colorectal cancer in attenuated FAP is unclear; the cumulative risk by age 80 years is estimated to be approximately 70% [Neklason et al 2008]. The average age of colon cancer diagnosis in individuals with attenuated FAP is 50 to 55 years — ten to 15 years later than in those with classic FAP, but earlier than in those with sporadically occurring colon cancer [Spirio et al 1993, Giardiello et al 1997].

In two large kindreds with attenuated FAP and an identical APC germline pathogenic variant [Burt et al 2004, Neklason et al 2008]:

  • The median number of adenomatous polyps in 120 individuals with pathogenic variants was 25 (range 0-470).
  • Forty-four (~37%) of 120 individuals with pathogenic variants for whom detailed colonoscopy records were available had fewer than ten adenomatous polyps.
  • Three of the 44 individuals with pathogenic variants who had fewer than ten polyps had colorectal cancer; one of the three was diagnosed before age 30 years.

Additional findings in attenuated FAP can include the following:

Genotype-Phenotype Correlations

Although variation occurs among individuals and among and within families with identical APC pathogenic variants [Giardiello et al 1994, Friedl et al 2001], much effort has gone into making genotype-phenotype correlations. Some have suggested basing management strategies on these associations [Vasen et al 1996], whereas others feel that therapeutic decisions should not be based on genotype [Friedl et al 2001].

While not in routine use at present the following correlations may become important in management decisions in the future (see Table 3 for reference sequences for pathogenic variants discussed in this section):

  • The most frequent APC pathogenic variant is located at codon 1309 (c.3927_3931delAAAGA) [Friedl & Aretz 2005]. Pathogenic variants at this codon lead to a high number of colonic adenomas at an early age [Friedl et al 2001, Bertario et al 2003].
  • The average age of onset in individuals with colonic symptoms [Friedl et al 2001] varied by pathogenic variant location:
    • At codon 1309: age 20 years
    • Between codon 168 and 1580 (excluding 1309): age 30 years
    • 5' of codon 168 and 3' of codon 1580: age 52 years
  • Profuse polyposis (an average of 5000 polyps) has been reported with pathogenic variants in codons 1250-1464 [Nagase et al 1992].
  • Attenuated FAP is associated with the following:
  • A fourfold increased risk for duodenal adenomas was found in individuals with pathogenic variants between codons 976 and 1067 in one study of Italian individuals with FAP [Bertario et al 2003].
  • Prominent extracolonic manifestations often correlate (though not completely) with more distal APC pathogenic variants. A retrospective study of 190 individuals with FAP that evaluated nine extracolonic manifestations (desmoid tumors, osteomas, epidermoid cysts, duodenal adenomas, gastric polyps, hepatoblastoma, dental anomalies, periampullary cancers, and brain tumors) [Wallis et al 1999] revealed that:
    • Individuals with pathogenic variants in codons 1395-1493 have significantly higher rates of desmoid tumors, osteomas, and epidermoid cysts than those with pathogenic variants in codons 177-452;
    • Individuals with pathogenic variants in codons 1395-1493 have significantly higher rates of desmoid tumors and osteomas than those with pathogenic variants in codons 457-1309;
    • No individuals with pathogenic variants in codons 177-452 developed osteomas or periampullary cancers;
    • Only individuals with pathogenic variants in codons 457-1309 developed hepatoblastoma and/or brain tumors.
  • Desmoid tumors show the following correlations:
    • After reviewing combined data on 2098 individuals with FAP, Sinha et al [2011] found that APC pathogenic variants 3’ to codon 1399 were associated with desmoid tumor development with an odds ratio of 4.37.
    • A study of 269 individuals with identifiable APC pathogenic variants found desmoid tumors in 20% of individuals with pathogenic variants 5' to codon 1444, 49% of individuals with pathogenic variants 3' to codon 1444, and 61% of individuals with pathogenic variants in codons 1445-1580 [Friedl et al 2001].
    • Several families with severe desmoid tumors with pathogenic variants at the extreme 3' end of the gene have been reported [Eccles et al 1996, Scott et al 1996, Couture et al 2000].
    • Nieuwenhuis & Vasen [2007] revealed a consistent association of desmoid tumors with pathogenic variants distal to codon 1444.
  • CHRPE is associated with:
  • In individuals with thyroid cancer and FAP:
    • In 24 individuals, the majority of pathogenic variants identified were 5' to codon 1220 [Cetta et al 2000];
    • Nine of 12 individuals had APC pathogenic variants identified proximal to the mutation cluster region (codons 1286-1513) [Truta et al 2003].
  • A review of the literature up to August 2006 and a report of additional cases by Nielsen et al [2007a] revealed 89 submicroscopic APC deletions (42 partial and 47 whole-gene deletions). Most partial and whole APC deletions are associated with 100-2000 colonic adenomas, although attenuated FAP has been seen [Nielsen et al 2007a]. Extracolonic findings were seen in 36% of cases, with no significant differences in those with partial vs. whole-gene deletions [Nielsen et al 2007a].

Penetrance

In FAP, the penetrance of colonic adenomatous polyposis and colon cancer is virtually 100% in untreated individuals.

In attenuated FAP, the penetrance of colonic polyposis is less well understood, although the estimate of colon cancer risk by age 80 years is approximately 70% [Neklason et al 2008].

See Clinical Description for penetrance related discussions for other intestinal and extraintestinal manifestations in APC-associated polyposis conditions.

Anticipation

Although a recent observation has suggested the possibility of anticipation in APC-associated polyposis conditions [Heald et al 2007], true genetic anticipation (in which subsequent generations are at an increased risk for more severe disease manifestations because of the underlying mutational mechanism) has not been observed in APC-associated polyposis conditions. Rather, milder disease manifestations in the first person to have the disorder in a family are most often the result of somatic mosaicism for the pathogenic variant in that individual.

Nomenclature

FAP is also known as familial polyposis coli. A term used historically for FAP is adenomatous polyposis coli (i.e., APC); APC now refers to the relevant gene.

The term Gardner syndrome is mainly of historical interest as it, like FAP, is now known to arise from pathogenic variants of APC. Furthermore, with sufficient investigation, subtle extraintestinal manifestations can be found in almost all individuals with FAP. Nonetheless, individuals and families with particularly prominent extracolonic manifestations will undoubtedly continue to be referred to as having Gardner syndrome.

In some families with FAP, multiple individuals have CNS tumors, making Turcot syndrome a historical term of uncertain significance as it relates to FAP. Turcot syndrome is also known as adenomatous polyposis coli with CNS tumors.

Attenuated FAP (also referred to as attenuated adenomatoous polyposis coli) appears to be the same as the “hereditary flat adenoma syndrome” [Lynch et al 1992].

Prevalence

The prevalence data reported from national registries include all of the APC-associated polyposis conditions (except possibly some cases of attenuated FAP); reported prevalence is 2.29 to 3.2 per 100,000 individuals [Burn et al 1991, Jarvinen 1992, Bülow et al 1996].

Attenuated FAP is likely underdiagnosed, given the lower number of colonic polyps and lower risk for colorectal cancer compared to classic FAP [Neklason et al 2008].

APC-associated polyposis conditions historically accounted for about 0.5% of all colorectal cancers; this figure is declining as more at-risk family members undergo successful treatment following early polyp detection and prophylactic colectomy.

Differential Diagnosis

APC-associated polyposis conditions may be distinguished from other inherited colon cancer conditions and other gastrointestinal polyposis syndromes by molecular genetic testing, histopathologic findings, and phenotypic characteristics. Hereditary disorders to consider in the differential diagnosis include the following:

  • MUTYH-associated polyposis (MAP). The colonic phenotype of MAP is similar to attenuated FAP but is inherited in an autosomal recessive manner. Germline biallelic pathogenic variants in MUTYH predispose individuals to multiple adenoma or polyposis coli. If an APC pathogenic variant is not identified in an individual with colonic polyposis, molecular genetic testing of MUTYH should be considered [Sieber et al 2003].

    Biallelic MUTYH pathogenic variants have been found in a few individuals diagnosed with colorectal cancer at age 50 years or younger who have had few or no polyps [Wang et al 2004]. The frequency of duodenal polyposis is between 4% and 25% among individuals with biallelic MUTYH pathogenic variants; extraintestinal findings are also noted on occasion [Aretz et al 2006].

    In one study of individuals with polyposis without an identified APC pathogenic variant, the detection rate of MUTYH pathogenic variants varied by the colonic severity [Aretz et al 2006]; biallelic MUTYH pathogenic variants were found in:
    • Forty (18%) of 227 individuals diagnosed with ten to 100 polyps after age 25 years or more than 100 polyps after age 45 years;
    • Seven (27%) of 26 individuals with more than 100 polyps diagnosed between ages 35 and 45 years;
    • None of 41 individuals with more than 100 polyps diagnosed before 35 years of age;
    • One individual with approximately 1,000 polyps diagnosed at age 68 years.
  • Lynch syndrome (hereditary non-polyposis colon cancer; HNPCC), primarily caused by a heterozygous germline pathogenic variant in one of four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2), is characterized by an increased risk for colorectal cancer and other cancers (e.g., of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, skin). It may be difficult to distinguish between Lynch syndrome and attenuated FAP in individuals with early-onset colorectal cancer and few adenomatous colonic polyps [Cao et al 2002]. In this situation, family history of extracolonic cancers and manifestations as well as microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) testing on a tumor block from a cancer may be helpful in deciding which condition is more likely.

    Biallelic pathogenic variants in the mismatch repair genes, although rare, have been reported. Affected individuals frequently have brain tumors, hematologic malignancies, and/or colorectal or other Lynch syndrome cancers in childhood [De Vos et al 2005, Felton et al 2007]. Café-au-lait spots and/or axillary/inguinal freckling are seen in most individuals, and multiple colorectal adenomas mimicking attenuated FAP may also be present [Felton et al 2007, Jasperson et al 2011].
  • Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal Peutz-Jeghers type polyps and mucocutaneous pigmentation, neither of which are present in APC-associated polyposis conditions. PJS polyps are often symptomatic and most prevalent in the small intestine (jejunum, ileum, and duodenum, respectively) but can occur elsewhere in the gastrointestinal tract. PJS is inherited in an autosomal dominant manner. Molecular genetic testing of STK11 reveals pathogenic variants in most cases.
  • PTEN hamartoma tumor syndrome (PHTS). Cowden syndrome (CS), the most common presentation of PHTS, is associated with multiple colorectal polyps, although unlike APC-associated polyposis conditions, hamartomatous polyps (juvenile polyps, lipomas and ganglioneuromas) predominate and colon cancer is an uncommon finding. Approximately 80% of individuals who meet the diagnostic criteria for CS have a detectable PTEN pathogenic variant.
  • Juvenile polyposis syndrome (JPS) is characterized by predisposition for hamartomatous polyps, which is often the distinguishing feature between the APC-associated polyposis conditions and JPS. The hamartomatous polyps occur in the GI tract, specifically in the stomach, small intestine, colon, and rectum. Most individuals with JPS have some polyps by age 20 years. Some individuals may have only four or five polyps over their lifetime; others in the same family may have more than 100. Most juvenile polyps are benign; however, malignant transformation can occur. JPS is inherited in an autosomal dominant manner. Approximately 20% of individuals with JPS have SMAD4 pathogenic variants, while 20% have BMPR1A pathogenic variants; none have been found to have APC pathogenic variants.
  • Hereditary mixed polyposis syndrome (HMPS) is associated with an increased risk for colorectal tumors and cancer. The characteristic lesions in HMPS are mixed juvenile-adenomatous colon polyps [Rozen et al 2003]. Additionally, adenomas, hyperplastic, serrated adenomas and mixed hyperplastic-adenomatous polyps may occur. Recently a duplication upstream of GREM1 has been implicated as the cause of HMPS [Jaeger et al 2012]. HMPS appears to be inherited in an autosomal dominant manner.
  • Neurofibromatosis type 1 (NF1). Individuals with NF1 may exhibit multiple intestinal polypoid neurofibromas or ganglioneuromas in the small bowel, stomach, and colon.

Acquired conditions to be considered in the differential diagnosis include the following:

  • Cronkhite-Canada syndrome, characterized by generalized gastrointestinal hamartomatous polyposis, cutaneous hyperpigmentation, hair loss, and nail atrophy
  • Nodular lymphoid hyperplasia, a lymphoproliferative disorder resulting in hyperplastic lymphoid nodules in small bowel, stomach, and colon; may be associated with common variable immunodeficiency syndrome
  • Lymphomatous polyposis, characterized by occurrence of primary extranodal lymphomas in the gastrointestinal tract. Two types include multiple lymphomatous polyposis and Mediterranean-type lymphoma.
  • Inflammatory polyposis, characterized by acquired, non-neoplastic polyps associated with inflammatory bowel disease, most commonly ulcerative colitis
  • Sporadic colorectal tumors. The majority of colorectal tumors not known to be familial have been associated with a somatic pathogenic variant in APC [Miyoshi et al 1992, Powell et al 1992, Smith et al 1993] that is believed to occur early in colorectal tumorigenesis [Fearon & Vogelstein 1990].
  • Therapy-associated polyposis was recently reported as a possible cause of gastrointestinal polyposis [Yurgelun et al 2013]. Five childhood cancer survivors, all treated with radiotherapy and chemotherapy, were reported to have gastrointestinal polyposis [Yurgelun et al 2013]. However, it is unclear whether the chemotherapy/radiation was causative of the gastrointestinal polyposis or coincidentally present in these five individuals.

Other:

  • Serrated polyposis (previously termed hyperplastic polyposis), comprising multiple colorectal serrated polyps (hyperplastic polyps, sessile serrated adenomas/polyps and traditional serrated adenomas). It is unknown whether this condition is inherited or acquired [Snover et al 2010]. Although serrated polyps typically predominate, individuals with serrated polyposis frequently have multiple colorectal adenomas [Kalady et al 2011]. Individuals with serrated polyposis may also have a family history of colorectal cancer, although it is uncommon for more than one member of a family to meet the diagnostic criteria for serrated polyposis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an APC-associated polyposis condition, the following evaluations are recommended:

  • Personal medical history with particular attention to features of APC-associated polyposis (colon cancer, colon polyps, rectal bleeding, diarrhea, abdominal pain)
  • Family history with particular attention to features of APC-associated polyposis
  • Physical examination with particular attention to extraintestinal manifestations of APC-associated polyposis
  • Ophthalmologic evaluation for presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE) (optional)
  • Colonoscopy with review of pathology
  • Consideration of upper GI tract evaluation, including endoscopy with a side-viewing scope; if symptomatic, small-bowel imaging such as small-bowel enteroclysis (an x-ray that looks at how contrast moves through the area) or abdominal and pelvic CT with contrast

Note: Smith et al [2000b] and Ferrández et al [2006] found no evidence to warrant screening for adrenal masses in FAP.

Treatment of Manifestations

Colonic polyps. Practice parameters, including information on surgery, have been outlined by the National Comprehensive Cancer Network (NCCN) [Burt et al 2013 (full text)], the American Society of Colon and Rectal Surgeons [Church et al 2003b (full text)], the American Society of Clinical Oncology [2003 (full text)], and the Society of Surgical Oncology [Guillem et al 2006 (full text)].

For individuals with classic FAP, colectomy is recommended after adenomas emerge; colectomy may be delayed depending on the size and number of adenomatous polyps. Colectomy is usually advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed.

For individuals with attenuated FAP, colectomy may be necessary, but in approximately one third of individuals the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient (see Surveillance).

Types of colectomy include the following:

  • Restorative proctocolectomy
  • Proctocolectomy with ileal pouch anal anastomosis
    • Stapled anastomosis without mucosectomy

      OR
    • Mucosectomy with handsewn anastomosis
  • Total colectomy with ileorectal anastomosis; often used for individuals with attenuated FAP or in instances in which the rectum is spared of polyps
  • Total proctocolectomy with permanent ileostomy
    Note: This procedure is rarely needed.

A study of individuals with FAP and ileal pouches found that 57% had adenomatous polyps in the ileal pouch. No apparent relationship between the development of pouch adenomas and the severity of polyps in the colon or duodenum was found [Groves et al 2005].

Cancer in the surgical transition zone has been reported [Ooi et al 2003] but very rarely occurs.

Small-bowel polyps. Endoscopic or surgical removal of duodenal and/or ampullary adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms [Wallace & Phillips 1998, Saurin et al 1999, Kadmon et al 2001].

Pancreaticoduodenectomy (Whipple procedure) may occasionally be necessary to treat severe duodenal adenomas.

Osteomas may be removed for cosmetic reasons.

Desmoid tumors. Available treatments include surgical excision (associated with high rates of recurrence), nonsteroidal anti-inflammatory drugs (NSAIDs), anti-estrogens, cytotoxic chemotherapy, and radiation [Griffioen et al 1998, Clark et al 1999, Smith et al 2000a, Tonelli et al 2003, Gega et al 2006]. A review of desmoid treatments can be found in Guillem et al [2006].

Nonsteroidal anti-inflammatory drugs (NSAIDs), especially sulindac [Steinbach et al 2000, Higuchi et al 2003, Keller & Giardiello 2003], have been shown to cause regression of adenomas in FAP and to decrease the number of polyps requiring ablation in the remaining rectum of individuals who have had a colectomy with ileorectal anastomosis.

Withdrawal from the market of rofecoxib in 2005 because of untoward cardiovascular and cerebrovascular events and the observation that similar events occur with the doses of celecoxib needed for adenoma regression has brought into question the long-term use of these agents for the treatment of FAP. Celecoxib at one time had an FDA-approved FAP indication as adjunct therapy; this indication has now been withdrawn due to concern over cardiovascular issues and lack of evidence of the effectiveness of this treatment with long-term follow up. Aspirin showed evidence of a modest effect on polyp regression in one study, but use of this agent in FAP requires much more study and is not yet recommended [Ishikawa et al 2014].

Note: NSAID use before colectomy remains experimental (see Therapies Under Investigation).

Prevention of Primary Manifestations

Colectomy is advised to reduce the risk for colorectal cancer when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed.

To reduce the risk for duodenal/periampullary adenocarcinoma, endoscopic or surgical removal of duodenal and/or ampullary adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms.

Surveillance

In individuals known to have FAP or an APC pathogenic variant and individuals at risk for FAP who have not undergone molecular genetic testing or are members of families in which molecular genetic testing did not identify a pathogenic variant [Giardiello et al 2001]:

  • Sigmoidoscopy or colonoscopy every one to two years, beginning at age ten to 12 years
  • Colonoscopy, once polyps are detected
  • Annual colonoscopy, if colectomy is delayed more than a year after polyps emerge. In individuals age ten to 20 years in whom adenomas are smaller than 6.0 mm and without villous component, delay in colectomy may be considered.
  • Esophagogastroduodenoscopy (EGD) beginning by age 25 years or prior to colectomy and repeated every one to three years

    Note: (1) The frequency of EGD depends on the severity of duodenal adenomas; Spigelman staging criteria can help determine the frequency. (2) A side-viewing instrument should be used to visualize the duodenal papilla. (3) As adenomatous tissue is commonly found at the papilla, biopsy may be justified if no polyps are visualized but the papilla seems enlarged. (4) In some cases, endoscopic retrograde cholangiopancreatography (ERCP) may be necessary to evaluate for adenomas of the common bile duct. (5) The utility of video capsule endoscopy (VCE) in screening for small-bowel lesions in FAP is unclear. Inaccurate identification of large polyps in the proximal small bowel and the inability to view the ampulla call into question the use of VCE in APC-associated polyposis conditions [Wong et al 2006]. In one small study, the ampulla was not observed in 21 (79% of) individuals with FAP who underwent VCE [Yamada et al 2014].
  • Small-bowel imaging (small-bowel enteroclysis or abdominal and pelvic CT with orally administered contrast) when duodenal adenomas are detected or prior to colectomy, repeated every one to three years depending on findings and presence of symptoms
  • Screening for hepatoblastoma: efficacy in individuals with FAP is unclear. Screening protocols in Beckwith-Wiedemann syndrome, in which the risk for hepatoblastoma is also increased, often include frequent (every 2-3 months) abdominal ultrasound examinations and measurement of serum alpha-fetoprotein concentrations and have resulted in early detection of hepatoblastomas [Tan & Amor 2006]. Screening for hepatoblastoma in FAP using the same protocol may be considered from infancy to age five years. However, the optimal interval for hepatoblastoma screening in FAP is not known, although it has been recommended that screening should occur at least every three months [Hirschman et al 2005, Aretz et al 2007].
  • Annual physical examination, including evaluation for extraintestinal manifestations, usually for cosmetic concerns, and palpation of the thyroid with consideration of follow-up ultrasound examination and fine-needle aspiration if thyroid nodules are present [Herraiz et al 2007]. Thyroid screening with ultrasound, even without clinical findings, may also be warranted, as none of the five affected individuals with thyroid cancer in one study were detected with neck examination [Jarrar et al 2011].

In individuals who have undergone colectomy

  • If total colectomy with ileo-anal pull-through was performed, routine endoscopic surveillance of the ileal pouch every two years
  • If subtotal colectomy was performed, surveillance of the remaining rectum every six to 12 months, depending on the number of polyps that develop. Cancer may still occur in the remaining rectum, but the risk is low with the current management [Church et al 2003a].

In individuals known to have attenuated FAP

  • Colonoscopy every two to three years, beginning at age 18 to 20 years
  • Colectomy: usually advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed (See In individuals who have undergone colectomy.)
  • Esophagogastroduodenoscopy (EGD) beginning by age 25 years or prior to colectomy and repeated every one to three years

    Note: (1) The frequency of EGD depends on the severity of duodenal adenomas; Spigelman staging criteria can help determine the frequency of exams. (2) A side-viewing instrument should be used to visualize the duodenal papilla. (3) Because adenomatous tissue is commonly found at the papilla, biopsy may be justified if no polyps are visualized but the papilla seems enlarged. (4) In some cases, endoscopic retrograde cholangiopancreatography (ERCP) may be necessary to evaluate for adenomas of the common bile duct.
  • Annual physical examination with palpation of the thyroid with consideration of follow-up ultrasound examination and fine-needle aspiration if thyroid nodules are present [Herraiz et al 2007]

In at-risk family members who, on molecular genetic testing, have not inherited the APC pathogenic variant previously identified in an affected family member:

  • Colon cancer screening for individuals at average risk beginning at age 50 years

Evaluation of Relatives at Risk

Recommended genetic testing for at-risk family members. Early recognition of APC-associated polyposis conditions may allow for timely intervention and improved final outcome; thus, surveillance of asymptomatic, at-risk children for early manifestations is appropriate [American Gastroenterological Association 2001 (full text), Hegde et al 2014 (full text)].

Use of molecular genetic testing for early identification of at-risk family members (see Genetic Counseling) improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant. A cost analysis comparing molecular genetic testing and sigmoidoscopy screening for individuals at risk for APC-associated polyposis conditions shows that genetic testing is more cost effective than sigmoidoscopy in determining who in the family is affected [Cromwell et al 1998]. Additionally, individuals diagnosed with APC-associated polyposis conditions as a result of having an affected relative have a significantly greater life expectancy than those individuals diagnosed on the basis of symptoms [Heiskanen et al 2000].

As colon screening for those at risk for classic FAP begins as early as age ten to 12 years, molecular genetic testing is generally offered to children at risk for classic FAP by age ten years. Genetic testing at birth may also be warranted, as some parents and pediatricians may consider hepatoblastoma screening from infancy to age five years in affected offspring. Colon screening for those with attenuated FAP begins at age 18 to 20 years; thus, molecular genetic testing should be offered to those at risk for attenuated FAP at approximately age 18 years.

Note: No evidence points to an optimal age at which to begin screening; thus, the ages at which testing is performed and screening initiated may vary by center, family history, hepatoblastoma screening, and/or the needs of the parents and/or child.

Therapies Under Investigation

In a small Phase I study, celecoxib reduced colorectal polyps in children with FAP pre-colectomy [Lynch et al 2010]. Celecoxib is associated with increased cardiovascular risk and therefore long-term safety is still a concern [Solomon et al 2008]. Although aspirin use in individuals with FAP showed a trend toward reduced polyp number and size in the CAPP1 (Colorectal Adenoma/Carcinoma Prevention Programme) study, the evidence did not support long-term aspirin use in affected individuals [Burn et al 2011].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

NSAIDs have been used unsuccessfully in an attempt to prevent the emergence of colonic adenomatous polyposis [Giardiello et al 2002].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

APC-associated polyposis conditions are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 20%-25% of individuals with an APC-associated polyposis condition have the altered gene as the result of de novo mutation [Bisgaard et al 1994].
  • Investigations to determine the parental origin of a de novo APC mutation suggest a slight preponderance of pathogenic variants of paternal origin (12/16 families; not statistically significant) [Aretz et al 2004] while another report shows equal maternal and paternal origin [Ripa et al 2002]. Thus, de novo APC mutations do not appear to demonstrate an advanced paternal age effect [Ripa et al 2002, Aretz et al 2004].
  • It is appropriate to evaluate the parents of an affected individual (a) with molecular genetic testing of APC if the pathogenic variant is known in the proband or (b) for clinical manifestations of APC-associated polyposis conditions.

Note: Although most individuals diagnosed with an APC-associated polyposis condition have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs depends on the genetic status of the parents.
  • If a parent is affected or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • If neither parent has the APC pathogenic variant identified in the proband, the risk to the sibs is low but greater than that of the general population because of the possibility of germline mosaicism. Thus, molecular genetic testing should be offered to the sibs of an individual with an apparent de novo mutation.
  • Germline mosaicism has been documented in an asymptomatic 79-year-old woman who had two sons with thousands of adenomatous colonic polyps and an APC pathogenic variant [Hes et al 2007]. Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an APC pathogenic variant [Schwab et al 2008].

Offspring of a proband. Every child of an individual with an APC-associated polyposis condition has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has an APC pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic individuals. Consideration of molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management, Evaluation of Relatives at Risk).

Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members when a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in APC.

The use of molecular genetic testing for determining the genetic status of at-risk relatives when a clinically diagnosed relative is not available for testing is problematic, and test results need to be interpreted with caution. A positive test result in the at-risk family member indicates the presence of an APC pathogenic variant and also indicates that the same molecular genetic testing method can be used to assess the genetic status of other, at-risk family members. In contrast, when genetic testing is offered to an at-risk family member prior to testing a family member known to be affected, the failure to identify a pathogenic variant in the at-risk family member does not eliminate the possibility that an APC pathogenic variant is present. The genetic status of such individuals cannot be determined through molecular genetic testing, and they need to follow the recommendations for clinical surveillance of at-risk family members.

Because colon screening for those at risk for classic FAP begins as early as age ten years, molecular genetic testing is generally offered to individuals by this age. Colon screening for those at risk for attenuated FAP begins at age 18 to 20 years; thus, molecular genetic testing should be offered at about age 18 years. Molecular genetic testing may be performed earlier if it alters medical management of the child, as is the case when parents are considering hepatoblastoma screening for their at-risk offspring. Predictive genetic testing may be considered within the first few months of life because of the increased risk for hepatoblastoma in FAP.

Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the altered gene. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and their children. Although most children do not show evidence of clinically significant psychological problems after presymptomatic testing, Codori et al [2003] recommend that long-term psychological support be available to these families.

Other issues to consider. It is recommended that physicians ordering APC molecular genetic testing and individuals considering undergoing testing understand the risks, benefits, and limitations of the testing prior to sending a sample to a laboratory. A study demonstrated that for almost one third of individuals assessed for FAP, the physician misinterpreted the test results [Giardiello et al 1997]. In addition, Michie et al [2002] found that at-risk relatives who were found not to have a pathogenic variant were more likely to request continued bowel surveillance when results were relayed to them by non-geneticist physicians than when they were relayed by genetics professionals. In a follow-up study evaluating why some at-risk individuals are not reassured by negative molecular genetic test results and request continued surveillance, Michie et al [2003] conclude that effective communication is key to facilitating adaptive behavior. Referral to a genetic counselor and/or a center in which testing is routinely offered is recommended.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ®, National Cancer Institute).

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing. The criteria for use of molecular genetic testing discussed in Testing of at-risk asymptomatic individuals apply to prenatal testing as well. It should be noted that detection of an APC pathogenic variant in a fetus at risk does not predict the time of onset or severity of the disease.

Requests for prenatal testing for conditions which (like the APC-associated polyposis conditions) do not affect intellect and have treatment available are not common. A pilot study of 20 individuals with FAP revealed that 100% believed it was ethical to provide prenatal testing for FAP, and 95% (19/20) would consider it themselves [Kastrinos et al 2007]. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) has been successfully used in pregnancies at risk for several inherited cancer predisposition syndromes and may be an option for couples at risk of having offspring with an APC-associated polyposis condition [Rechitsky et al 2002, Davis et al 2006, Moutou et al 2007]. The parent's disease-causing allele must be identified before PGD can be performed.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA)
  • Familial Adenomatous Polyposis Foundation
    P.O. Box 2005
    Park City UT 84060
    Phone: 334-740-8657
    Email: info@fapfoundation.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Library of Medicine Genetics Home Reference
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • C3: Colorectal Cancer Coalition
    1414 Prince Street
    Suite 204
    Alexandria VA 22314
    Phone: 877-427-2111 (toll-free); 703-548-1225
    Fax: 202-315-3871
    Email: info@fightcolorectalcancer.org
  • Colon Cancer Alliance (CCA)
    1200 G Street Northwest
    Suite 800
    Washington DC 20005
    Phone: 877-422-2030 (Toll-free Helpline); 202-434-8980
    Fax: 866-304-9075 (toll-free)
  • Desmoid Tumor Research Foundation (DTRF)
    P.O. Box 273
    Suffern NY 10901
    Email: marlene@dtrf.org
  • United Ostomy Associations of America, Inc. (UOAA)
    PO Box 66
    Fairview TN 37062-0066
    Phone: 800-826-0826 (toll-free)
    Email: info@uoaa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. APC-Associated Polyposis Conditions: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for APC-Associated Polyposis Conditions (View All in OMIM)

175100FAMILIAL ADENOMATOUS POLYPOSIS 1; FAP1
611731APC GENE; APC

Gene structure. APC is alternatively spliced in multiple coding and non-coding regions; the primary transcript NM_000038.5 has 15 coding exons that code for 2843 amino acids and result in a 311.8-kd protein. The last coding exon is large and comprises more than three quarters of the coding region of the gene. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 826 germline pathogenic variants have been found in families with an APC-associated polyposis condition [Beroud et al 2000]. Pathogenic variants almost always cause a premature truncation of the APC protein, usually through single amino-acid substitutions or frameshifts. While pathogenic variants have been found scattered throughout the gene, they are predominantly located in the 5' end of the gene. The most common germline APC pathogenic variant is c.3927_3931delAAAGA. (For more information, see Table A.)

Table 3. Selected APC Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
Benignc.5465T>Ap.Val1822Asp
(p.Asp1822Val)
NM_000038​.5
NP_000029​.2
Uncertain clinical significancec.3949G>Cp.Glu1317Gln
Predisposition to colon cancerc.3920T>Ap.Ile1307Lys
Pathogenicc.3927_3931delAAAGAp.Glu1309AspfsTer4

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The APC protein has been localized to the nucleus and membrane/cytoskeleton in human epithelial cells [Neufeld & White 1997]. It has also been shown to homodimerize [Joslyn et al 1993] and bind to other proteins including GSK3b [Rubinfeld et al 1996], beta-catenin [Rubinfeld et al 1993, Su et al 1993], gamma-catenin [Hulsken et al 1994, Rubinfeld et al 1995], tubulin [Munemitsu et al 1994, Smith et al 1994], EB1 [Su et al 1995], and hDLG, a homolog of the Drosophila discs large tumor-suppressor protein [Matsumine et al 1996]. The APC protein product is a tumor suppressor. APC protein forms a complex with glycogen synthase kinase 3b (GSK-3b) [Rubinfeld et al 1996], which targets beta-catenin, a protein involved in both cell adhesion and intracellular signal transduction [Korinek et al 1997, Morin et al 1997, Nakamura 1997, Peifer 1997, Rubinfeld et al 1997]. The presence of normal APC protein appears to maintain normal apoptosis and may also decrease cell proliferation, probably through its regulation of beta-catenin. This pathway is normally involved with Wingless-Wnt signaling, which participates in several known cell growth functions.

The APC protein has been shown to accumulate at the kinetochore during mitosis, contribute to kinetochore-microtubule attachment, and play a role in chromosome segregation in mouse embryonic stem cells [Fodde et al 2001, Kaplan et al 2001]. The APC protein may play a role in chromosomal instability, the presence of which is often observed when APC function is lost.

Other possible roles for the APC protein include: regulation of cell migration up the colonic crypt and cell adhesion through association with E-cadherin, regulation of cell polarity through association with GSK3b, and other functions related to association with microtubule bundles [Nathke et al 1996, Barth et al 1997, Etienne-Manneville & Hall 2003]. Goss & Groden [2000] provide an excellent review of the function of the APC protein.

Abnormal gene product. Pathogenic variants in APC most often result in truncated protein products. Experiments have localized normal full-length APC protein to the membrane/cytoskeleton and nuclear fractions of human epithelial cells but demonstrated that colon cancer cells containing only mutant APC genes revealed no truncated APC protein in nuclear fractions [Neufeld & White 1997].

For APC pathogenic alleles that produce an abnormal protein, high levels of free cytosolic beta-catenin are observed. Free beta-catenin migrates to the nucleus, binds to a transcription factor Tcf-4 or Lef-1 (T cell factor-lymphoid enhancer factor), and may activate expression of genes such as the oncogenes c-Myc and cyclin D1 [Chung 2000]. The specific genes targeted are not yet known but may include those increasing proliferation or decreasing apoptosis. Because APC may be important in cell migration, abnormal APC protein may disrupt normal cellular positioning in the colonic crypt. Additionally, pathogenic variants in APC are thought to contribute to chromosomal instability in colorectal cancers [Fodde et al 2001].

References

Published Guidelines/Consensus Statements

  1. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Available online. 2014. Accessed 3-18-14.
  2. American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing. Available online. 2001. Accessed 3-18-14.
  3. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2003. Accessed 3-18-14.
  4. American Society of Clinical Oncology/Society of Surgical Oncology review of current role of risk-reducing surgery in common hereditary cancer syndromes. Available online. 2006. Accessed 3-18-14.
  5. American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Available online. 2003. Accessed 3-18-14.
  6. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 3-18-14.
  7. Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Available online. 2001. Accessed 3-18-14.
  8. National Comprehensive Cancer Network Colorectal Cancer Screening Clinical Practice Guidelines in Oncology. Available online. 2013. Accessed 3-18-14.
  9. Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucii J, Ganiats T, Levin T, Woolf S, Johnson D, Kirk L, Litin S, Simmang C for the US Multisociety Task Force on Colorectal Cancer. Colorectal cancer screening and surveillance: clinical guidelines and rationale - Update based on new evidence. American Gastroenterological Association. Available online. 2003. Accessed 3-18-14.

Literature Cited

  1. American Gastroenterological Association; American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:195–7. [PubMed: 11438508]
  2. Aretz S, Stienen D, Friedrichs N, Stemmler S, Uhlhaas S, Rahner N, Propping P, Friedl W. Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP). Hum Mutat. 2007;28:985–92. [PubMed: 17486639]
  3. Aretz S, Stienen D, Uhlhaas S, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W. Large submicroscopic genomic APC deletions are a common cause of typical familial adenomatous polyposis. J Med Genet. 2005;42:185–92. [PMC free article: PMC1736002] [PubMed: 15689459]
  4. Aretz S, Uhlhaas S, Caspari R, Mangold E, Pagenstecher C, Propping P, Friedl W. Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis. Eur J Hum Genet. 2004;12:52–8. [PubMed: 14523376]
  5. Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer. 2006;119:807–14. [PubMed: 16557584]
  6. Aretz S, Vasen HF, Olschwang S. Clinical utility gene card for: familial adenomatous polyposis (FAP) and attenuated FAP (AFAP). Eur J Hum Genet. 2011;19(7) [PMC free article: PMC3137508] [PubMed: 21368914]
  7. Attard TM, Giardiello FM, Argani P, Cuffari C. Fundic gland polyposis with high-grade dysplasia in a child with attenuated familial adenomatous polyposis and familial gastric cancer. J Pediatr Gastroenterol Nutr. 2001;32:215–8. [PubMed: 11321399]
  8. Barth AI, Pollack AL, Altschuler Y, Mostov KE, Nelson WJ. NH2-terminal deletion of beta-catenin results in stable colocalization of mutant beta-catenin with adenomatous polyposis coli protein and altered MDCK cell adhesion. J Cell Biol. 1997;136:693–706. [PMC free article: PMC2134296] [PubMed: 9024698]
  9. Beroud C, Collod-Beroud G, Boileau C, Soussi T, Junien C. UMD (Universal mutation database): a generic software to build and analyze locus-specific databases. Hum Mutat. 2000;15:86–94. [PubMed: 10612827]
  10. Bertario L, Russo A, Sala P, Eboli M, Giarola M. Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer. 2001;95:102–7. [PubMed: 11241320]
  11. Bertario L, Russo A, Sala P, Varesco L, Giarola M, Mondini P, Pierotti M, Spinelli P, Radice P. Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis. J Clin Oncol. 2003;21:1698–707. [PubMed: 12721244]
  12. Bisgaard ML, Fenger K, Bulow S, Niebuhr E, Mohr J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat. 1994;3:121–5. [PubMed: 8199592]
  13. Brett MCA, Hershman MJ, Glazer G. Other manifestations of familial adenomatous polyposis. In: Phillips RKS, Spiegelman AD, Thomson JPS, eds. Familial Adenomatous Polyposis and Other Polyposis Syndromes. London, UK: Edward Arnold; 1994:143-60.
  14. Bülow S, Alm T, Fausa O, Hultcrantz R, Järvinen H, Vasen H, Bülow S, Alm T, Fausa O, Hultcrantz R, Jarvinen H, Vasen H. Duodenal adenomatosis in familial adenomatous polyposis. DAF Project Group. Int J Colorectal Dis. 1995;10:43–6. [PubMed: 7745323]
  15. Bülow S, Faurschou Nielsen T, Bülow C, Bisgaard ML, Karlsen L, Moesgaard F. The incidence rate of familial adenomatous polyposis. Results from the Danish Polyposis Register. Int J Colorectal Dis. 1996;11:88–91. [PubMed: 8739833]
  16. Bunyan DJ, Eccles DM, Sillibourne J, Wilkins E, Thomas NS, Shea-Simonds J, Duncan PJ, Curtis CE, Robinson DO, Harvey JF, Cross NC. Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification. Br J Cancer. 2004;91:1155–9. [PMC free article: PMC2747696] [PubMed: 15475941]
  17. Burger B, Cattani N, Trueb S, de Lorenzo R, Albertini M, Bontognali E, Itin C, Schaub N, Itin PH, Heinimann K. Prevalence of skin lesions in familial adenomatous polyposis: a marker for presymptomatic diagnosis? Oncologist. 2011;16:1698–705. [PMC free article: PMC3248768] [PubMed: 22135120]
  18. Burn J, Bishop DT, Chapman PD, Elliott F, Bertario L, Dunlop MG, Eccles D, Ellis A, Evans DG, Fodde R, Maher ER, Möslein G, Vasen HF, Coaker J, Phillips RK, Bülow S, Mathers JC. A randomized placebo-controlled prevention trial of aspirin and/or resistant starch in young people with familial adenomatous polyposis. Cancer Prev Res (Phila). 2011;4:655–65. [PMC free article: PMC3092423] [PubMed: 21543343]
  19. Burn J, Chapman P, Delhanty J, Wood C, Lalloo F, Cachon-Gonzalez MB, Tsioupra K, Church W, Rhodes M, Gunn A. The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations. J Med Genet. 1991;28:289–96. [PMC free article: PMC1016845] [PubMed: 1650842]
  20. Burt RW. Gastric fundic gland polyps. Gastroenterology. 2003;125:1462–9. [PubMed: 14598262]
  21. Burt RW, Cannon JA, David DS, Early DS, Ford JM, Giardiello FM, Halverson AL, Hamilton SR, Hampel H, Ismail MK, Jasperson K, Klapman JB, Lazenby AJ, Lynch PM, Mayer RJ, Ness RM, Provenzale D, Rao MS, Shike M, Steinbach G, Terdiman JP, Weinberg D, Dwyer M, Freedman-Cass D. Colorectal cancer screening. J Natl Compr Canc Netw. 2013;11:1538–75. [PubMed: 24335688]
  22. Burt RW, Leppert MF, Slattery ML, Samowitz WS, Spirio LN, Kerber RA, Kuwada SK, Neklason DW, Disario JA, Lyon E, Hughes JP, Chey WY, White RL. Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology. 2004;127:444–51. [PubMed: 15300576]
  23. Burt RW, Ward K, Spirio L. et al. Accurate identification of familial adenomatous polyposis coli using newly developed genetic markers. Gastroenterology. 1992;102:A347.
  24. Bussey HJR. Familial Polyposis Coli. Baltimore, MD: Johns Hopkins University Press; 1975.
  25. Cao Y, Pieretti M, Marshall J, Khattar NH, Chen B, Kam-Morgan L, Lynch H. Challenge in the differentiation between attenuated familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer: case report with review of the literature. Am J Gastroenterol. 2002;97:1822–7. [PubMed: 12135043]
  26. Cetta F, Montalto G, Gori M, Curia MC, Cama A, Olschwang S. Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study. J Clin Endocrinol Metab. 2000;85:286–92. [PubMed: 10634400]
  27. Chen CS, Phillips KD, Grist S, Bennet G, Craig JE, Muecke JS, Suthers GK. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in familial colorectal cancer. Fam Cancer. 2006;5:397–404. [PubMed: 16944273]
  28. Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology. 2000;119:854–65. [PubMed: 10982779]
  29. Church J, Burke C, McGannon E, Pastean O, Clark B. Risk of rectal cancer in patients after colectomy and ileorectal anastomosis for familial adenomatous polyposis: a function of available surgical options. Dis Colon Rectum. 2003a;46:1175–81. [PubMed: 12972960]
  30. Church J, Simmang C. Standards Task Force, American Society of Colon and Rectal Surgeons, Collaborative Group of the Americas on Inherited Colorectal Cancer and the Standards Committee of The American Society of Colon and Rectal Surgeons.; Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. 2003b;46:1001–12. [PubMed: 12907889]
  31. Church JM, McGannon E. Prior pregnancy ameliorates the course of intra-abdominal desmoid tumors in patients with familial adenomatous polyposis. Dis Colon Rectum. 2000;43:445–50. [PubMed: 10789737]
  32. Clark SK, Neale KF, Landgrebe JC, Phillips RK. Desmoid tumours complicating familial adenomatous polyposis. Br J Surg. 1999;86:1185–9. [PubMed: 10504375]
  33. Clark SK, Phillips RK. Desmoids in familial adenomatous polyposis. Br J Surg. 1996;83:1494–504. [PubMed: 9014661]
  34. Codori AM, Zawacki KL, Petersen GM, Miglioretti DL, Bacon JA, Trimbath JD, Booker SV, Picarello K, Giardiello FM. Genetic testing for hereditary colorectal cancer in children: long-term psychological effects. Am J Med Genet. 2003;116A:117–28. [PubMed: 12494429]
  35. Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000;57:205–12. [PubMed: 10782927]
  36. Cromwell DM, Moore RD, Brensinger JD, Petersen GM, Bass EB, Giardiello FM. Cost analysis of alternative approaches to colorectal screening in familial adenomatous polyposis. Gastroenterology. 1998;114:893–901. [PubMed: 9558276]
  37. Davis T, Song B, Cram DS. Preimplantation genetic diagnosis of familial adenomatous polyposis. Reprod Biomed Online. 2006;13:707–11. [PubMed: 17169185]
  38. De Vos M, Hayward B, Bonthron DT, Sheridan E. Phenotype associated with recessively inherited mutations in DNA mismatch repair (MMR) genes. Biochem Soc Trans. 2005;33:718–20. [PubMed: 16042583]
  39. Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996;59:1193–201. [PMC free article: PMC1914868] [PubMed: 8940264]
  40. Etienne-Manneville S, Hall A. Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature. 2003;421:753–6. [PubMed: 12610628]
  41. Evans DG, Guy SP, Thakker N, Armstrong JG, Dodd C, Davies DR, Babbs C, Clancy T, Warnes T, Sloan P, Taylor TV, Harris R. Non-penetrance and late appearance of polyps in families with familial adenomatous polyposis. Gut. 1993;34:1389–93. [PMC free article: PMC1374547] [PubMed: 8244107]
  42. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67. [PubMed: 2188735]
  43. Felton KE, Gilchrist DM, Andrew SE. Constitutive deficiency in DNA mismatch repair: is it time for Lynch III? Clin Genet. 2007;71:499–500. [PubMed: 17539898]
  44. Ferrández A, Pho L, Solomon C, Samowitz WS, Kuwada SK, Knecht TP, Gilfeather M, Burt RW. An evidence-based, multidisciplinary approach to the clinical considerations, management, and surveillance of adrenal lesions in familial adenomatous polyposis: report of three cases. Dis Colon Rectum. 2006;49:1781–90. [PubMed: 17041748]
  45. Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C, van Es JH, Breukel C, Wiegant J, Giles RH, Clevers H. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol. 2001;3:433–8. [PubMed: 11283620]
  46. Friedl W, Aretz S. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005;3:95–114. [PMC free article: PMC2837297] [PubMed: 20223039]
  47. Friedl W, Caspari R, Sengteller M, Uhlhaas S, Lamberti C, Jungck M, Kadmon M, Wolf M, Fahnenstich J, Gebert J, Moslein G, Mangold E, Propping P. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut. 2001;48:515–21. [PMC free article: PMC1728231] [PubMed: 11247896]
  48. Friedl W, Meuschel S, Caspari R, Lamberti C, Krieger S, Sengteller M, Propping P. Attenuated familial adenomatous polyposis due to a mutation in the 3' part of the APC gene. A clue for understanding the function of the APC protein. Hum Genet. 1996;97:579–84. [PubMed: 8655134]
  49. Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet. 1953;5:139–47. [PMC free article: PMC1716470] [PubMed: 13065261]
  50. Garrean S, Hering J, Saied A, Jani J, Espat NJ. Gastric adenocarcinoma arising from fundic gland polyps in a patient with familial adenomatous polyposis syndrome. Am Surg. 2008;74:79–83. [PubMed: 18274437]
  51. Gega M, Yanagi H, Yoshikawa R, Noda M, Ikeuchi H, Tsukamoto K, Oshima T, Fujiwara Y, Gondo N, Tamura K, Utsunomiya J, Hashimoto-Tamaoki T, Yamamura T. Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol. 2006;24:102–5. [PubMed: 16382119]
  52. Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:198–213. [PubMed: 11438509]
  53. Giardiello FM, Brensinger JD, Petersen GM, Luce MC, Hylind LM, Bacon JA, Booker SV, Parker RD, Hamilton SR. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med. 1997;336:823–7. [PubMed: 9062090]
  54. Giardiello FM, Hylind LM, Trimbath JD, Hamilton SR, Romans KE, Cruz-Correa M, Corretti MC, Offerhaus GJ, Yang VW. Oral contraceptives and polyp regression in familial adenomatous polyposis. Gastroenterology. 2005;128:1077–80. [PubMed: 15825088]
  55. Giardiello FM, Krush AJ, Petersen GM, Booker SV, Kerr M, Tong LL, Hamilton SR. Phenotypic variability of familial adenomatous polyposis in 11 unrelated families with identical APC gene mutation. Gastroenterology. 1994;106:1542–7. [PubMed: 8194700]
  56. Giardiello FM, Offerhaus GJ, Lee DH, Krush AJ, Tersmette AC, Booker SV, Kelley NC, Hamilton SR. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993;34:1394–6. [PMC free article: PMC1374548] [PubMed: 8244108]
  57. Giardiello FM, Yang VW, Hylind LM, Krush AJ, Petersen GM, Trimbath JD, Piantadosi S, Garrett E, Geiman DE, Hubbard W, Offerhaus GJ, Hamilton SR. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med. 2002;346:1054–9. [PMC free article: PMC2225537] [PubMed: 11932472]
  58. Goss KH, Groden J. Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol. 2000;18:1967–79. [PubMed: 10784639]
  59. Griffioen G, Bus PJ, Vasen HF, Verspaget HW, Lamers CB. Extracolonic manifestations of familial adenomatous polyposis: desmoid tumours, and upper gastrointestinal adenomas and carcinomas. Scand J Gastroenterol Suppl. 1998;225:85–91. [PubMed: 9515758]
  60. Groves CJ, Beveridge G, Swain DJ, Saunders BP, Talbot IC, Nicholls RJ, Phillips RK. Prevalence and morphology of pouch and ileal adenomas in familial adenomatous polyposis. Dis Colon Rectum. 2005;48:816–23. [PubMed: 15747076]
  61. Guillem JG, Wood WC, Moley JF, Berchuck A, Karlan BY, Mutch DG, Gagel RF, Weitzel J, Morrow M, Weber BL, Giardiello F, Rodriguez-Bigas MA, Church J, Gruber S, Offit K. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol. 2006;24:4642–60. [PubMed: 17008706]
  62. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, Burger PC, Wood PA, Taqi F, Booker SV, Petersen GM, Offerhaus GJA, Tersmette AC, Giardiello FM, Vogelstein B, Kinzler KW. The molecular basis of Turcot's syndrome. N Engl J Med. 1995;332:839–47. [PubMed: 7661930]
  63. Heald B, Moran R, Milas M, Burke C, Eng C. Familial adenomatous polyposis in a patient with unexplained mental retardation. Nat Clin Pract Neurol. 2007;3:694–700. [PubMed: 18046442]
  64. Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A. Working Group of the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee.; ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014;16:101–16. [PubMed: 24310308]
  65. Heiskanen I, Luostarinen T, Jarvinen HJ. Impact of screening examinations on survival in familial adenomatous polyposis. Scand J Gastroenterol. 2000;35:1284–7. [PubMed: 11199368]
  66. Herraiz M, Barbesino G, Faquin W, Chan-Smutko G, Patel D, Shannon KM, Daniels GH, Chung DC. Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations. Clin Gastroenterol Hepatol. 2007;5:367–73. [PubMed: 17258512]
  67. Hes FJ, Nielsen M, Bik EC, Konvalinka D, Wijnen JT, Bakker E, Vasen HF, Breuning MH, Tops CM. Somatic APC mosaicism: an underestimated cause of polyposis coli. Gut. 2007;57:71–6. [PubMed: 17604324]
  68. Higuchi T, Iwama T, Yoshinaga K, Toyooka M, Taketo MM, Sugihara K. A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients. Clin Cancer Res. 2003;9:4756–60. [PubMed: 14581346]
  69. Hirschman BA, Pollock BH, Tomlinson GE. The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr. 2005;147:263–6. [PubMed: 16126064]
  70. Hofgartner WT, Thorp M, Ramus MW, Delorefice G, Chey WY, Ryan CK, Takahashi GW, Lobitz JR. Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis. Am J Gastroenterol. 1999;94:2275–81. [PubMed: 10445562]
  71. Hulsken J, Behrens J, Birchmeier W. Tumor-suppressor gene products in cell contacts: the cadherin-APC-armadillo connection. Curr Opin Cell Biol. 1994;6:711–6. [PubMed: 7833051]
  72. Ishikawa H, Mutoh M, Suzuki S, Tokudome S, Saida Y, Abe T, Okamura S, Tajika M, Joh T, Tanaka S, Kudo SE, Matsuda T, Iimuro M, Yukawa T, Takayama T, Sato Y, Lee K, Kitamura S, Mizuno M, Sano Y, Gondo N, Sugimoto K, Kusunoki M, Goto C, Matsuura N, Sakai T, Wakabayashi K. The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial. Gut. 2014 [PubMed: 24488498]
  73. Jaeger E, Leedham S, Lewis A, Segditsas S, Becker M, Cuadrado PR, Davis H, Kaur K, Heinimann K, Howarth K, East J, Taylor J, Thomas H, Tomlinson I. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet. 2012;44:699–703. [PubMed: 22561515]
  74. Jarrar AM, Milas M, Mitchell J, Laguardia L, O'Malley M, Berber E, Siperstein A, Burke C, Church JM. Sreening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg. 2011;253:515–21. [PubMed: 21173694]
  75. Jarvinen HJ. Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut. 1992;33:357–60. [PMC free article: PMC1373827] [PubMed: 1314763]
  76. Jasperson K, Samowitz W, Burt R. Constitutional mismatch repair-deficiency syndrome presenting as colonic adenomatous polyposis: clues from the skin. Clin Genet. 2011;80:394–7. [PubMed: 21039432]
  77. Johansen C, Bitsch M, Bülow S. Fertility and pregnancy in women with familial adenomatous polyposis. Int J Colorectal Dis. 1990;5:203–6. [PubMed: 1962811]
  78. Joslyn G, Richardson DS, White R, Alber T. Dimer formation by an N-terminal coiled coil in the APC protein. Proc Natl Acad Sci USA. 1993;90:11109–13. [PMC free article: PMC47931] [PubMed: 8248216]
  79. Kadmon M, Tandara A, Herfarth C. Duodenal adenomatosis in familial adenomatous polyposis coli. A review of the literature and results from the Heidelberg Polyposis Register. Int J Colorectal Dis. 2001;16:63–75. [PubMed: 11355321]
  80. Kalady MF, Jarrar A, Leach B, LaGuardia L, O'Malley M, Eng C, Church JM. Defining phenotypes and cancer risk in hyperplastic polyposis syndrome. Dis Colon Rectum. 2011;54:164–70. [PubMed: 21228663]
  81. Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Nathke IS. A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat Cell Biol. 2001;3:429–32. [PubMed: 11283619]
  82. Kastrinos F, Stoffel EM, Balmaña J, Syngal S. Attitudes toward prenatal genetic testing in patients with familial adenomatous polyposis. Am J Gastroenterol. 2007;102:1284–90. [PubMed: 17355417]
  83. Keller JJ, Giardiello FM. Chemoprevention strategies using NSAIDs and COX-2 inhibitors. Cancer Biol Ther. 2003;2:S140–9. [PubMed: 14508092]
  84. Knudsen AL, Bisgaard ML, Bülow S. Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer. 2003;2:43–55. [PubMed: 14574166]
  85. Knudsen AL, Bülow S, Tomlinson I, Möslein G, Heinimann K, Christensen IJ. AFAP Study Group; Attenuated familial adenomatous polyposis: results from an international collaborative study. Colorectal Dis. 2010;12:e243–9. [PubMed: 20105204]
  86. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997;275:1784–7. [PubMed: 9065401]
  87. Lefevre JH, Rodrigue CM, Mourra N, Bennis M, Flejou JF, Parc R, Tiret E, Gespach C, Parc YR. Implication of MYH in colorectal polyposis. Ann Surg. 2006;244:874–9. [PMC free article: PMC1856630] [PubMed: 17122612]
  88. Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch PM, Jenkins JX, Rouse J, Cavalieri J, Howard L, Lynch J. Hereditary flat adenoma syndrome: a variant of familial adenomatous polyposis? Dis Colon Rectum. 1992;35:411–21. [PubMed: 1314729]
  89. Lynch PM, Ayers GD, Hawk E, Richmond E, Eagle C, Woloj M, Church J, Hasson H, Patterson S, Half E, Burke CA. The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol. 2010;105:1437–43. [PubMed: 20234350]
  90. Marchesa P, Fazio VW, Church JM, McGannon E. Adrenal masses in patients with familial adenomatous polyposis. Dis Colon Rectum. 1997;40:1023–8. [PubMed: 9293929]
  91. Matsumine A, Ogai A, Senda T, Okumura N, Satoh K, Baeg GH, Kawahara T, Kobayashi S, Okada M, Toyoshima K, Akiyama T. Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein. Science. 1996;272:1020–3. [PubMed: 8638125]
  92. Michie S, Collins V, Halliday J, Marteau TM. Likelihood of attending bowel screening after a negative genetic test result: the possible influence of health professionals. Genet Test. 2002;6:307–11. [PubMed: 12537655]
  93. Michie S, Smith JA, Senior V, Marteau TM. Understanding why negative genetic test results sometimes fail to reassure. Am J Med Genet. 2003;119A:340–7. [PubMed: 12784302]
  94. Michils G, Tejpar S, Thoelen R, van Cutsem E, Vermeesch JR, Fryns JP, Legius E, Matthijs G. Large deletions of the APC gene in 15% of mutation-negative patients with classical polyposis (FAP): a Belgian study. Hum Mutat. 2005;25:125–34. [PubMed: 15643602]
  95. Middleton SB, Clark SK, Matravers P, Katz D, Reznek R, Phillips RK. Stepwise progression of familial adenomatous polyposis-associated desmoid precursor lesions demonstrated by a novel CT scoring system. Dis Colon Rectum. 2003;46:481–5. [PubMed: 12682541]
  96. Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992;1:229–33. [PubMed: 1338904]
  97. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90. [PubMed: 9065402]
  98. Moutou C, Gardes N, Nicod JC, Viville S. Strategies and outcomes of PGD of familial adenomatous polyposis. Mol Hum Reprod. 2007;13:95–101. [PubMed: 17114207]
  99. Munemitsu S, Souza B, Muller O, Albert I, Rubinfeld B, Polakis P. The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res. 1994;54:3676–81. [PubMed: 8033083]
  100. Nagase H, Miyoshi Y, Horii A, Aoki T, Ogawa M, Utsunomiya J, Baba S, Sasazuki T, Nakamura Y. Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res. 1992;52:4055–7. [PubMed: 1319838]
  101. Nakamura Y. Cleaning up on beta-catenin. Nat Med. 1997;3:499–500. [PubMed: 9142114]
  102. Nathke IS, Adams CL, Polakis P, Sellin JH, Nelson WJ. The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J Cell Biol. 1996;134:165–79. [PMC free article: PMC2120913] [PubMed: 8698812]
  103. Neklason DW, Stevens J, Boucher KM, Kerber RA, Matsunami N, Barlow J, Mineau G, Leppert MF, Burt RW. American founder mutation for attenuated familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2008;6:46–52. [PMC free article: PMC2245898] [PubMed: 18063416]
  104. Neufeld KL, White RL. Nuclear and cytoplasmic localizations of the adenomatous polyposis coli protein. Proc Natl Acad Sci U S A. 1997;94:3034–9. [PMC free article: PMC20317] [PubMed: 9096341]
  105. Nielsen M, Bik E, Hes FJ, Breuning MH, Vasen HF, Bakker E, Tops CM, Weiss MM. Genotype-phenotype correlations in 19 Dutch cases with APC gene deletions and a literature review. Eur J Hum Genet. 2007a;15:1034–42. [PubMed: 17568392]
  106. Nielsen M, Hes FJ, Nagengast FM, Weiss MM, Mathus-Vliegen EM, Morreau H, Breuning MH, Wijnen JT, Tops CM, Vasen HF. Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. Clin Genet. 2007b;71:427–33. [PubMed: 17489848]
  107. Nieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol. 2007;61:153–61. [PubMed: 17064931]
  108. Nieuwenhuis MH, Casparie M, Mathus-Vliegen LM, Dekkers OM, Hogendoorn PC, Vasen HF. A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses. Int J Cancer. 2011a;129:256–61. [PubMed: 20830713]
  109. Nieuwenhuis MH, Douma KF, Bleiker EM, Bemelman WA, Aaronson NK, Vasen HF. Female fertility after colorectal surgery for familial adenomatous polyposis: a nationwide cross-sectional study. Ann Surg. 2010;252:341–4. [PubMed: 20622653]
  110. Nieuwenhuis MH, Mathus-Vliegen EM, Baeten CG, Nagengast FM, van der Bijl J, van Dalsen AD, Kleibeuker JH, Dekker E, Langers AM, Vecht J, Peters FT, van Dam R, van Gemert WG, Stuifbergen WN, Schouten WR, Gelderblom H, Vasen HF. Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients. Int J Cancer. 2011b;129:256–61. [PubMed: 20830713]
  111. Offerhaus GJ, Entius MM, Giardiello FM. Upper gastrointestinal polyps in familial adenomatous polyposis. Hepatogastroenterology. 1999;46:667–9. [PubMed: 10370594]
  112. Olsen KO, Juul S, Bülow S, Jarvinen HJ, Bakka A, Bjork J, Oresland T, Laurberg S. Female fecundity before and after operation for familial adenomatous polyposis. Br J Surg. 2003;90:227–31. [PubMed: 12555301]
  113. Ooi BS, Remzi FH, Gramlich T, Church JM, Preen M, Fazio VW. Anal transition zone cancer after restorative proctocolectomy and ileoanal anastomosis in familial adenomatous polyposis: report of two cases. Dis Colon Rectum. 2003;46:1418–23. [PubMed: 14530685]
  114. Peifer M. Beta-catenin as oncogene: the smoking gun. Science. 1997;275:1752–3. [PubMed: 9122680]
  115. Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991;100:1658–64. [PubMed: 1673441]
  116. Pilarski RT, Brothman AR, Benn P, Shulman Rosengren S. Attenuated familial adenomatous polyposis in a man with an interstitial deletion of chromosome arm 5q. Am J Med Genet. 1999;86:321–4. [PubMed: 10494086]
  117. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, Kinzler KW. APC mutations occur early during colorectal tumorigenesis. Nature. 1992;359:235–7. [PubMed: 1528264]
  118. Pujol RM, Casanova JM, Egido R, Pujol J, de Moragas JM. Multiple familial pilomatricomas: a cutaneous marker for Gardner syndrome? Pediatr Dermatol. 1995;12:331–5. [PubMed: 8747580]
  119. Rechitsky S, Verlinsky O, Chistokhina A, Sharapova T, Ozen S, Masciangelo C, Kuliev A, Verlinsky Y. Preimplantation genetic diagnosis for cancer predisposition. Reprod Biomed Online. 2002;5:148–55. [PubMed: 12419039]
  120. Rekik NM, Ben Salah S, Kallel N, Kamoun M, Charfi N, Abid M. Adrenocortical secreting mass in a patient with Gardner's syndrome: a case report. Case Report Med. 2010; 2010:682081.
  121. Ripa R, Bisgaard ML, Bülow S, Nielsen FC. De novo mutations in familial adenomatous polyposis (FAP). Eur J Hum Genet. 2002;10:631–7. [PubMed: 12357334]
  122. Rohlin A, Engwall Y, Fritzell K, Göransson K, Bergsten A, Einbeigi Z, Nilbert M, Karlsson P, Björk J, Nordling M. Inactivation of promoter 1B of APC causes partial gene silencing: evidence for a significant role of the promoter in regulation and causative of familial adenomatous polyposis. Oncogene. 2011;30:4977–89. [PMC free article: PMC3240859] [PubMed: 21643010]
  123. Rozen P, Samuel Z, Shomrat R, Legum C. Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9. Gut. 1999;45:829–33. [PMC free article: PMC1727742] [PubMed: 10562580]
  124. Rozen P, Samuel Z, Brazowski E. A prospective study of the clinical, genetic, screening, and pathologic features of a family with hereditary mixed polyposis syndrome. Am J Gastroenterol. 2003;98:2317–20. [PubMed: 14572586]
  125. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272:1023–6. [PubMed: 8638126]
  126. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science. 1997;275:1790–2. [PubMed: 9065403]
  127. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P. Association of the APC gene product with beta-catenin. Science. 1993;262:1731–4. [PubMed: 8259518]
  128. Rubinfeld B, Souza B, Albert I, Munemitsu S, Polakis P. The APC protein and E-cadherin form similar but independent complexes with alpha-catenin, beta-catenin, and plakoglobin. J Biol Chem. 1995;270:5549–55. [PubMed: 7890674]
  129. Ruys AT, Alderlieste YA, Gouma DJ, Dekker E, Mathus-Vliegen EM. Jejunal cancer in patients with familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2010;8:731–3. [PubMed: 20399906]
  130. Saurin JC, Chayvialle JA, Ponchon T. Management of duodenal adenomas in familial adenomatous polyposis. Endoscopy. 1999;31:472–8. [PubMed: 10494690]
  131. Schwab AL, Tuohy TM, Condie M, Neklason DW, Burt RW. Gonadal mosaicism and familial adenomatous polyposis. Fam Cancer. 2008;7:173–7. [PubMed: 18026870]
  132. Scott RJ, Froggatt NJ, Trembath RC, Evans DG, Hodgson SV, Maher ER. Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation. Hum Mol Genet. 1996;5:1921–4. [PubMed: 8968744]
  133. Sieber OM, Lamlum H, Crabtree MD, Rowan AJ, Barclay E, Lipton L, Hodgson S, Thomas HJW, Neale K, Phillips RKS, Farrington SM, Dunlop MG, Mueller HJ, Bisgaard ML, Bülow S, Fidalgo P, Albuquerque C, Scarano MI, Bodmer W, Tomlinson IPM, Heinimann K. Whole-gene APC deletions cause classical familial adnomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas. PNAS. 2002;99:2954–8. [PMC free article: PMC122454] [PubMed: 11867715]
  134. Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, Bisgaard ML, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJ, Tomlinson IP. Multiple colorectal adenomas, classic adenomatous polyposis, and germ- line mutations in MYH. N Engl J Med. 2003;348:791–9. [PubMed: 12606733]
  135. Sieber OM, Segditsas S, Knudsen AL, Zhang J, Luz J, Rowan AJ, Spain SL, Thirlwell C, Howarth KM, Jaeger EE, Robinson J, Volikos E, Silver A, Kelly G, Aretz S, Frayling I, Hutter P, Dunlop M, Guenther T, Neale K, Phillips R, Heinimann K, Tomlinson IP. Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. Gut. 2006;55:1440–8. [PMC free article: PMC1856441] [PubMed: 16461775]
  136. Sinha A, Tekkis PP, Gibbons DC, Phillips RK, Clark SK. Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta-analysis. Colorectal Dis. 2011;13:1222–9. [PubMed: 20528895]
  137. Smith AJ, Lewis JJ, Merchant NB, Leung DH, Woodruff JM, Brennan MF. Surgical management of intra-abdominal desmoid tumours. Br J Surg. 2000a;87:608–13. [PubMed: 10792318]
  138. Smith KJ, Johnson KA, Bryan TM, Hill DE, Markowitz S, Willson JK, Paraskeva C, Petersen GM, Hamilton SR, Vogelstein B, Kinzler KW. The APC gene product in normal and tumor cells. Proc Natl Acad Sci USA. 1993;90:2846–50. [PMC free article: PMC46193] [PubMed: 8385345]
  139. Smith KJ, Levy DB, Maupin P, Pollard TD, Vogelstein B, Kinzler KW. Wild-type but not mutant APC associates with the microtubule cytoskeleton. Cancer Res. 1994;54:3672–5. [PubMed: 8033082]
  140. Smith TG, Clark SK, Katz DE, Reznek RH, Phillips RK. Adrenal masses are associated with familial adenomatous polyposis. Dis Colon Rectum. 2000b;43:1739–42. [PubMed: 11156460]
  141. Snover DC, Ahnen DJ, Burt RW, Odze RD. Serrated polyps of the colon and rectum and serrated polyposis. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System. 4 ed. Lyon, France: IARC; 2010:160-5.
  142. Solomon SD, Wittes J, Finn PV, Fowler R, Viner J, Bertagnolli MM, Arber N, Levin B, Meinert CL, Martin B, Pater JL, Goss PE, Lance P, Obara S, Chew EY, Kim J, Arndt G, Hawk E. Cross Trial Safety Assessment Group; Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008;117:2104–13. [PMC free article: PMC2965408] [PubMed: 18378608]
  143. Soravia C, Berk T, Madlensky L, Mitri A, Cheng H, Gallinger S, Cohen Z, Bapat B. Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet. 1998;62:1290–301. [PMC free article: PMC1377162] [PubMed: 9585611]
  144. Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RK. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet. 1989;2:783–5. [PubMed: 2571019]
  145. Spirio L, Olschwang S, Groden J, Robertson M, Samowitz W, Joslyn G, Gelbert L, Thliveris A, Carlson M, Otterud B, Lynch H, Watson P, Lynch P, Laurent-Puig P, Burt R, Hughes JP, Thomas G, Leppert M, White R. Alleles of the APC gene: an attenuated form of familial polyposis. Cell. 1993;75:951–7. [PubMed: 8252630]
  146. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342:1946–52. [PubMed: 10874062]
  147. Steinhagen E, Guillem JG, Chang G, Salo-Mullen EE, Shia J, Fish S, Stadler ZK, Markowitz AJ. The prevalence of thyroid cancer and benign thyroid disease in patients with familial adenomatous polyposis may be higher than previously recognized. Clin Colorectal Cancer. 2012;11:304–8. [PubMed: 22425061]
  148. Su LK, Burrell M, Hill DE, Gyuris J, Brent R, Wiltshire R, Trent J, Vogelstein B, Kinzler KW. APC binds to the novel protein EB1. Cancer Res. 1995;55:2972–7. [PubMed: 7606712]
  149. Su LK, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science. 1993;262:1734–7. [PubMed: 8259519]
  150. Suraweera N, Latchford A, McCart A, Rogers P, Spain S, Sieber O, Phillips R, Tomlinson I, Silver A. Pregnancy does not influence colonic polyp multiplicity but may modulate upper gastrointestinal disease in patients with FAP. J Med Genet. 2007;44:541–4. [PMC free article: PMC2597927] [PubMed: 17496195]
  151. Tan TY, Amor DJ. Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health. 2006;42:486–90. [PubMed: 16925531]
  152. Tonelli F, Ficari F, Valanzano R, Brandi ML. Treatment of desmoids and mesenteric fibromatosis in familial adenomatous polyposis with raloxifene. Tumori. 2003;89:391–6. [PubMed: 14606641]
  153. Truta B, Allen BA, Conrad PG, Kim YS, Berk T, Gallinger S, Bapat B, Terdiman JP, Sleisenger MH. Genotype and phenotype of patients with both familial adenomatous polyposis and thyroid carcinoma. Fam Cancer. 2003;2:95–9. [PubMed: 14574158]
  154. Truta B, Allen BA, Conrad PG, Weinberg V, Miller GA, Pomponio R, Lipton LR, Guerra G, Tomlinson IP, Sleisenger MH, Kim YS, Terdiman JP. A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history. Fam Cancer. 2005;4:127–33. [PubMed: 15951963]
  155. van der Luijt RB, Meera Khan P, Vasen HF, Breukel C, Tops CM, Scott RJ, Fodde R. Germline mutations in the 3' part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli. Hum Genet. 1996;98:727–34. [PubMed: 8931709]
  156. van der Luijt RB, Vasen HF, Tops CM, Breukel C, Fodde R, Meera Khan P. APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis. Hum Genet. 1995;96:705–10. [PubMed: 8522331]
  157. Vasen HF, van der Luijt RB, Slors JF, Buskens E, de Ruiter P, Baeten CG, Schouten WR, Oostvogel HJ, Kuijpers JH, Tops CM, Meera Khan P. Molecular genetic tests as a guide to surgical management of familial adenomatous polyposis. Lancet. 1996;348:433–5. [PubMed: 8709782]
  158. Wallace MH, Phillips RK. Upper gastrointestinal disease in patients with familial adenomatous polyposis. Br J Surg. 1998;85:742–50. [PubMed: 9667698]
  159. Wallerstein RJ, Brooks SS, Streck DL, Kurvathi R, Toruner GA. Exclusion of APC and VHL gene deletions by array-based comparative hybridization in two patients with microscopically visible chromosomal aberrations. Cancer Genet Cytogenet. 2007;178:151–4. [PubMed: 17954272]
  160. Wallis YL, Morton DG, McKeown CM, Macdonald F. Molecular analysis of the APC gene in 205 families: extended genotype- phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition. J Med Genet. 1999;36:14–20. [PMC free article: PMC1762945] [PubMed: 9950360]
  161. Walon C, Kartheuser A, Michils G, Smaers M, Lannoy N, Ngounou P, Mertens G, Verellen-Dumoulin C. Novel germline mutations in the APC gene and their phenotypic spectrum in familial adenomatous polyposis kindreds. Hum Genet. 1997;100:601–5. [PubMed: 9341879]
  162. Wang L, Baudhuin LM, Boardman LA, Steenblock KJ, Petersen GM, Halling KC, French AJ, Johnson RA, Burgart LJ, Rabe K, Lindor NM, Thibodeau SN. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004;127:9–16. [PubMed: 15236166]
  163. Wehrli BM, Weiss SW, Yandow S, Coffin CM. Gardner-associated fibromas (GAF) in young patients: a distinct fibrous lesion that identifies unsuspected Gardner syndrome and risk for fibromatosis. Am J Surg Pathol. 2001;25:645–51. [PubMed: 11342777]
  164. Wong RF, Tuteja AK, Haslem DS, Pappas L, Szabo A, Ogara MM, DiSario JA. Video capsule endoscopy compared with standard endoscopy for the evaluation of small-bowel polyps in persons with familial adenomatous polyposis (with video). Gastrointest Endosc. 2006;64:530–7. [PubMed: 16996344]
  165. Yamada A, Watabe H, Iwama T, Obi S, Omata M, Koike K. The prevalence of small intestinal polyps in patients with familial adenomatous polyposis: a prospective capsule endoscopy study. Fam Cancer. 2014;13:23–8. [PubMed: 23743563]
  166. Yurgelun MB, Hornick JL, Curry VK, Ukaegbu CI, Brown EK, Hiller E, Chittenden A, Goldberg JE, Syngal S. Therapy-associated polyposis as a late sequela of cancer treatment. Clin Gastroenterol Hepatol. 2013 Dec 19. pii: S1542-3565(13)01967-8.
  167. Zwick A, Munir M, Ryan CK, Gian J, Burt RW, Leppert M, Spirio L, Chey WY. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology. 1997;113:659–63. [PubMed: 9247488]

Suggested Reading

  1. Bunz F, Kinzler KW, Vogelstein B. Colorectal tumors. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 48. Available online. Accessed 3-18-14.
  2. Olschwang S. Familial adenomatous polyposis (FAP). Atlas of Genetics and Cytogenetics Oncology and Haematology. Available at online. 1998. Accessed 3-18-14.

Chapter Notes

Author History

Randall W Burt, MD (1998-present)
Kory W Jasperson, MS (2008-present)
Cindy Solomon, MS; Myriad Genetic Laboratories (1998-2008)

Revision History

  • 27 March 2014 (me) Comprehensive update posted live
  • 27 October 2011 (me) Comprehensive update posted live
  • 24 July 2008 (me) Comprehensive update posted live
  • 21 October 2005 (me) Comprehensive update posted to live Web site
  • 20 September 2004 (chs) Revision: new clinical method
  • 27 May 2004 (chs) Revision: Genetic Counseling - genetic cancer subsection added
  • 15 March 2004 (me) Comprehensive update posted to live Web site
  • 23 June 2003 (cd) Revision: terminology
  • 18 January 2002 (me) Comprehensive update posted to live Web site
  • 18 December 1998 (pb) Review posted to live Web site
  • 11 September 1998 (ch) Original submission
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