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MUTYH-Associated Polyposis

Synonyms: Colorectal Adenomatous Polyposis, Autosomal Recessive; Multiple Colorectal Adenomas, Autosomal Recessive; MYH-Associated Polyposis

, MD, , MD, , MS, CGC, and , MD.

Author Information

Initial Posting: ; Last Update: September 24, 2015.

Summary

Clinical characteristics.

MUTYH-associated polyposis (MAP), caused by biallelic pathogenic variants in MUTYH, is characterized by a greatly increased lifetime risk of colorectal cancer (CRC) (43% to almost 100% in the absence of timely surveillance). Although typically associated with ten to a few hundred colonic adenomatous polyps that are evident at a mean age of about 50 years, colonic cancer develops in some individuals with biallelic MUTYH pathogenic variants in the absence of polyposis. Duodenal adenomas are found in 17%-25% of individuals with MAP. Serrated adenomas, hyperplastic/sessile serrated polyps, and mixed (hyperplastic and adenomatous) polyps can also occur. The lifetime risk of duodenal cancer is about 4%. Also noted are a modestly increased risk for rather late-onset malignancies of the ovary, bladder, and skin, and some evidence for an increased risk for breast and endometrial cancer. Some affected individuals develop sebaceous gland tumors and more recently, thyroid abnormalities (multinodular goiter, single nodules, and papillary thyroid cancer) have been reported.

Diagnosis/testing.

The diagnosis is established in individuals with characteristic clinical findings and biallelic germline MUTYH pathogenic variants.

Management.

Treatment of manifestations: Suspicious polyps identified on colonoscopy should be removed until polypectomy alone cannot manage the large size and density of the polyps, at which point either subtotal colectomy or proctocolectomy is performed. Duodenal polyps showing dysplasia or villous changes should be excised during endoscopy. Abnormal findings on thyroid ultrasound examination should be evaluated by a thyroid specialist to determine what combination of monitoring, surgery, and/or fine needle aspiration (FNA) is appropriate.

Surveillance: Individuals with biallelic germline MUTYH pathogenic variants:

  • In the US: pan colonoscopy every one to two years beginning at age 25-30 years; following colectomy, endoscopy of any remaining colon or rectum every one to two years. Upper endoscopy and side viewing duodenoscopy beginning at age 30-35 years with subsequent follow up based on initial findings, analogous to FAP using the Spigelman criteria. No consensus exists for screening for thyroid abnormalities. For extraintestinal malignancies surveillance is as for existing protocols offered to the general population.
  • In Europe: pan colonoscopy beginning at age 18-20 years; upper endoscopy with side viewing duodenoscopy beginning at age 25-30 years; follow up depending on disease severity using the Spigelman criteria.
  • Individuals with a heterozygous germline MUTYH pathogenic variant: offer average moderate-risk colorectal screening based on family history.

Evaluation of relatives at risk: Offer molecular genetic testing for the familial pathogenic variants to all sibs of an individual with genetically confirmed MAP in order to reduce morbidity and mortality through early diagnosis and treatment.

Genetic counseling.

MAP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier with a small increased risk for CRC, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis

Suggestive Findings

MUTYH-associated polyposis (MAP) should be suspected in an individual with the following clinical findings and molecular genetic findings on tumor tissue.

Clinical findings

  • Colonic adenoma and/or hyperplastic/serrated sessile polyp count:
    • Between one and ten (age <40 years)
    • More than ten (age 40-60 years)
    • More than 20 (age >60 years)
  • Colonic adenoma and/or hyperplastic/serrated sessile polyp count between twenty and a few hundred
  • Colonic polyposis (i.e., >100 colonic polyps) in the absence of a heterozygous germline APC pathogenic variant
  • CRC diagnosed in an individual younger than age 40 years
  • Family history of colon cancer (± polyps) consistent with autosomal recessive inheritance

Histologic and molecular genetic findings on tumor tissue

Establishing the Diagnosis

The diagnosis of MAP is established in a proband by the identification of biallelic MUTYH pathogenic variants [Al-Tassan et al 2002, Sieber et al 2003] (see Table 1).

Molecular testing approaches can include single-gene testing and use of a multi-gene panel.

Table 1.

Molecular Genetic Testing Used in MUTYH-Associated Polyposis

Gene 1Test Method 2Proportion of Probands with Pathogenic Variants 3 Detectable by This Method
MUTYHSequence analysis 4~99% 5
Gene-targeted deletion/duplication analysis 6Unknown 7
1.
2.

Information on test sensitivity, specificity, and other test characteristics can be found online [Aretz et al 2013].

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.
6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

The pathogenic variant detection rate for exon or whole-gene deletions or duplications appears low; only one deletion has been reported to date. Three groups reported the same large (>4.2 kb) deletion encompassing exons 4-16 in three different affected individuals from Spain, France, and Brazil, indicating a possible southern Europe founder variant [Rouleau et al 2011, Torrezan et al 2011, Castillejo et al 2014].

Likelihood of identifying biallelic germline MUTYH pathogenic variants by number of polyps. See Table 2.

Table 2.

Biallelic Germline MUTYH Pathogenic Variant Detection Frequency by Number of Polyps in Individuals with APC Mutation-Negative Polyposis

Number of PolypsBiallelic Pathogenic Variant Detection Frequency
1-190% (0/1240)
10-194% (37/970)
10-495% (3/62)
10-9926% (113/435)
20-997% (233/3253)
100-9997%-14% (94/1338 1 and 52/370 2)
>10002% (2/119)

Likelihood of identifying biallelic germline MUTYH pathogenic variants by age of person with CRCs. See Table 3.

Table 3.

Percentage of Persons with CRC with Biallelic Germline MUTYH Pathogenic Variants by Age at Diagnosis

Persons with Biallelic MUTYH Pathogenic Variants
% (n)RangeAge at Diagnosis of CRC
1.4% (48/3526)0.8%-6.2%<50 years
0.3% (28/11150)0.0%-0.6%>50 years

CRC = colorectal cancer

Clinical Characteristics

Clinical Description

Colon polyps. Most individuals with MUTYH-associated polyposis (MAP) have between ten and a few hundred polyps with a mean age of presentation of approximately 50 years.

A number of individuals with MAP have been described with colorectal cancer (CRC) and no polyps or only a few polyps [Croitoru et al 2004, Farrington et al 2005, Balaguer et al 2007, Cleary et al 2009]. In a minority (0%-3.7%) of affected individuals, MUTYH biallelic pathogenic variants have been found in the index case of a clinical Lynch or Lynch-like family [Nielsen et al 2011, Castillejo et al 2014].

Persons with MAP can present with conventional adenomas as well as serrated adenomas, hyperplastic/sessile serrated polyps, and mixed (hyperplastic and adenomatous) polyps [Sieber et al 2003, Chow et al 2006, Boparai et al 2008, O’Shea et al 2008]. Of note, in eight of 17 persons with MAP one or more hyperplastic polyps and/or sessile serrated adenomas were found. Three of these eight individuals fulfilled the criteria for the serrated polyposis syndrome (see Differential Diagnosis) [Boparai et al 2008].

Colon cancer. In the absence of timely surveillance, the lifetime risk for CRC in MAP ranges between 43% and almost 100% [Sampson et al 2003, Sieber et al 2003, Gismondi et al 2004, Farrington et al 2005, Lubbe et al 2009].

Colon cancers were found to be right-sided in 29% to 69% of individuals with MAP [Lipton et al 2003, O’Shea et al 2008, Nielsen et al 2009a].

Metachronous or synchronous colon cancers occur in 23% to 27% of individuals [Lipton et al 2003, Nielsen et al 2009a].

In one report, individuals with MAP had better survival on average than controls. Five-year survival for persons with MAP colorectal cancer was 78% (95% confidence interval (CI): 70%-84%) and for controls was 63% (95% CI: 56%-69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for persons with MAP-associated CRC than for controls (hazard ratio of death: 0.48; 95% CI: 0.32-0.72) [Nielsen et al 2010].

Other features variably present in MUTYH-associated polyposis

Duodenal polyps and cancer. Duodenal polyps are found in 17%-25% of individuals with MAP. The lifetime risk for duodenal cancer is approximately 4% (standardized incidence ratio (SIR): 129; 95% CI: 16-466) [Sieber et al 2003, Aretz et al 2006, Nielsen et al 2006, Vogt et al 2009].

Gastric fundic gland polyps and gastric cancer. Among 150 individuals with MAP undergoing endoscopic surveillance, 17 (11%) had gastric lesions. Although a higher risk for gastric cancer was observed than in the general population, the trend was not significant (3 of 150; SIR: 4.2; 95% CI: 0.9-12) [Vogt et al 2009].

Extraintestinal manifestations. According to the study of Vogt et al [2009] of 276 persons with MAP from 181 unrelated families, the incidence of extraintestinal malignancies in persons with MAP was almost twice that of the general population (SIR: 1.9; 95% CI: 1.4-2.5); however, no predominant tumor type or marked shift toward early onset was observed. Approximately 28% of the affected individuals had at least one of the following extraintestinal findings:

  • Ovarian cancer. The incidence was significantly increased (SIR: 5.7; 95% CI: 1.2-17). Mean age at diagnosis was 51 years.
  • Bladder cancer. The incidence was significantly increased (SIR: 7.2; 95% CI: 2.0-18). Mean age at diagnosis was 61 years.
  • Breast cancer. In women the risk for breast cancer tended to be increased. Mean age at diagnosis was 53 years. Breast cancer was also diagnosed in one male with biallelic germline MUTYH pathogenic variants.
  • Endometrial cancer. Cancer of the endometrium was found in two of 118 women. The mean age at diagnosis was 51 years.
  • Skin findings. Benign and malignant sebaceous gland tumors were found in five of 98 individuals and all of these also presented with the associated polyposis coli phenotype (>20 adenomas). Six of 98 had skin cancers (melanomas, squamous epithelial carcinomas, and basal cell cancers) (SIR: 2.8; 95% CI: 1.5-4.8); another eight had other benign tumors of the skin (fibrous histiocytoma, capillary hemangioma, pilar cyst, dermatofibroma, and follicle cyst).
  • Thyroid findings
    • Two individuals with thyroid cancer were found in a cohort of 276 persons with MAP; a third individual with thyroid cancer has been reported elsewhere [Ponti et al 2005, Vogt et al 2009]. However, further investigation is warranted.
    • A recent study performed by the Cleveland Clinic revealed that 16 of 24 individuals with biallelic germline MUTYH pathogenic variants had abnormal thyroid ultrasound examinations: 7/16 had multinodular goiter and 6/16 had a single nodule. Three of 24 were diagnosed with papillary thyroid cancer [LaGuardia et al 2011]. Note: This high incidence of thyroid cancer was not found in any other study and may point to possible selection bias.
  • Dental abnormalities. Jaw-bone cysts have been reported in 11 of 276 persons with MAP [Vogt et al 2009].
  • Congenital hypertrophy of retinal pigment epithelium (CHRPE). The estimate of CHRPE in individuals with MAP is about 5.5%; however, this figure may also include misdiagnoses since pigment anomalies of the retina are quite frequent in the general population [Vogt et al 2009].

MUTYH heterozygotes. The risk of developing CRC in individuals with a heterozygous germline MUTYH pathogenic variant is unclear. The risk was found to be only marginally increased in large population-based studies (OR: 1.1-1.2 in meta-analyses), whereas family-based studies found a higher risk in MUTYH heterozygote family members than in the general population (OR: 2-3) [Jenkins et al 2006, Jones et al 2009]. Another more recent large family-based study consisting of 9504 relatives found that through age 70 years, CRC risk was 7.2% for males heterozygous for a MUTYH pathogenic variant and 5.6% for females heterozygous for a MUTYH pathogenic variant, independent of family history. For individuals heterozygous for a MUTYH pathogenic variant with a first-degree relative with CRC, diagnosed by age 50 years, without confirmed MAP (i.e., untested, no MUTYH pathogenic variant, or a heterozygous MUTYH pathogenic variant), the risk of CRC was 12.5% for men and 10% for women [Win et al 2014]. This finding supports following individuals with a heterozygous germline MUTYH pathogenic variant more intensively with recommendations based on their family history (every 5 years).

Genotype-Phenotype Correlations

Several studies indicate that homozygosity for the c.536A>G pathogenic variant confers risk for a more severe phenotype and earlier age of onset as compared with homozygosity for c.1187G>A; age at onset of CRC is approximately eight years earlier for c.536A>G homozygotes [Lubbe et al 2009, Nielsen et al 2009b, Terdiman 2009, Morak et al 2010].

Nomenclature

MYH-associated polyposis is an outdated term. MYH was changed to MUTYH. (see Molecular Genetics, Gene structure). This term should no longer be used.

Another term that is no longer appropriate is autosomal recessive adenomatous polyposis.

Penetrance

Among nearly 20,000 controls tested to date, only one unaffected individual with biallelic germline MUTYH pathogenic variants has been reported [Lubbe et al 2009, Nielsen et al 2011].

The penetrance of CRC in individuals with biallelic germline MUTYH pathogenic variants is high, but incomplete, at age 60 years [Farrington et al 2005, Lubbe et al 2009].

The penetrance of colorectal polyposis is unknown. Molecular genetic testing of individuals with CRC has revealed that up to one third of persons who have biallelic germline MUTYH pathogenic variants develop CRC in the absence of polyposis, suggesting incomplete penetrance [Croitoru et al 2004, Farrington et al 2005, Balaguer et al 2007, Cleary et al 2009].

Prevalence

It is estimated that 1%-2% of the general northern European population is heterozygous for a germline MUTYH pathogenic variant [Al-Tassan et al 2002, Jones et al 2002, Sampson et al 2003, Sieber et al 2003, Cleary et al 2009]. From this figure a prevalence of 1:40,000 to 1:20,000 for persons with biallelic germline pathogenic variants can be derived.

Due to the presence of founder pathogenic variants, ethnicity-specific prevalence rates are likely to exist. For example, in populations from Far East Asia less frequent MUTYH pathogenic variants have been reported [Kim et al 2007, Yanaru-Fujisawa et al 2008].

MAP is estimated to account for 0.7% of all CRC, and up to 2% of familial or early-onset CRC cohorts in which affected individuals have a low number of adenomas (<15-20) [Sieber et al 2003, Cleary et al 2009, Lubbe et al 2009].

Differential Diagnosis

MUTYH-associated polyposis (MAP) can be distinguished from other inherited polyposis and colon cancer conditions by clinical findings, pathogenic findings, mode of inheritance, and molecular genetic testing. Conditions to consider in the differential diagnosis include the following:

APC-associated polyposis conditions, caused by a heterozygous germline APC pathogenic variant, are inherited in an autosomal dominant manner. The APC-related polyposis phenotypes similar in presentation to MAP are:

  • Attenuated familial adenomatous polyposis (AFAP), often the genetic syndrome most closely related in presentation to MAP, is caused by a pathogenic variant at the 5’ or 3’ end of APC. Individuals with AFAP have between 0 and 100 (mean: 30) adenomas generally located proximally within the colon, and/or a delayed onset of disease compared to classic familial adenomatous polyposis. Adenomas of the upper segment of the GI tract may also be present. The risk for colon cancer is increased, with diagnosis of colon cancer typically in the fourth or fifth decade.
  • Familial adenomatous polyposis (FAP) is generally characterized by more than 100 adenomas of the colon with onset at an average age of 16 years. Polyps of the small bowel and fundic gland are also common. Without surgical intervention, colon cancer is inevitable (average age 39 years). Individuals with FAP are also at an increased risk for small bowel, gastric, pancreatic, thyroid, CNS, liver, and bile duct cancers. Other findings may include desmoid tumors of the abdomen, supernumerary or missing teeth, osteomas, epidermoid cysts, and CHRPE (congenital hypertrophy of the retinal pigment epithelium).

NTHL1- associated polyposis (OMIM), caused by homozygous germline NTHL1 pathogenic variants, is inherited in an autosomal recessive manner. NTHL1- associated polyposis is the second most common autosomal recessive form of colon cancer and polyps after MAP; seven affected individuals with adenomatous polyposis (range 8-50 polyps) from three unrelated families have been reported. Four of these individuals were diagnosed with CRC (age range 40-67 years), each of them having multiple CRCs. Individuals with NTHL1- associated polyposis are also at increased risk for endometrial cancer, premalignant endometrial lesions, duodenal adenomas, and duodenal cancer [Weren et al 2015]. Further studies are needed to characterize this newly described disorder.

Lynch syndrome (hereditary non-polyposis colon cancer, HNPCC) is characterized by an increased risk for colon, uterine, ovarian, stomach, small bowel, hepatobiliary tract, urinary tract, brain, and skin cancers. The risk for colorectal cancer is the highest cancer risk seen in Lynch syndrome (52%-82% lifetime risk, mean age at diagnosis 44-61 years), and colon tumors generally exhibit microsatellite instability. A recent study reporting on lifetime cumulative risk for adenomas in Lynch syndrome found that 4% of individuals develop ten or more polyps [Kalady et al 2015]. Lynch syndrome is caused by a heterozygous germline pathogenic variant in a mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) or a germline deletion in EPCAM and is inherited in an autosomal dominant manner.

Peutz-Jeghers syndrome (PJS) is characterized by GI hamartomatous polyps and mucocutaneous pigmentation. Polyps are most often in the small bowel. Mucocutaneous pigmentation appears as dark brown to dark blue spots that often fade with age. Individuals with PJS are also at an increased risk for colon, gastric, breast, lung, pancreas, and sex organ cancers. A heterozygous pathogenic variant in STK11 can be detected in up to 94% of individuals with PJS [Aretz et al 2005]. Inheritance is autosomal dominant.

Juvenile polyposis syndrome (JPS) is characterized by an increased risk for hamartomatous polyps of the GI tract. JPS can be diagnosed clinically by the presence of more than five juvenile polyps of the colon, multiple juvenile polyps throughout the GI tract, or any number of juvenile polyps and a family history of juvenile polyps. The term juvenile reflects the histology of the polyps rather than the age of onset. Hamartomatous polyps generally present in the small bowel, stomach, colon, and rectum. Juvenile polyps are benign, but malignancies can occur. Risk for GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have also been reported. The genes known to be associated with JPS are BMPR1A and SMAD4. Approximately 20% of individuals with JPS have a pathogenic variant in BMPR1A; approximately 20% have a pathogenic variant in SMAD4. Inheritance is autosomal dominant. Individuals with a SMAD4 germline pathogenic variant are also at increased risk for hereditary hemorrhagic telangiectasia.

PTEN hamartoma tumor syndromes (PHTS) include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRB), and PTEN-related Proteus syndrome (PS). CS is characterized by multiple hamartomatous polyps in the GI tract and increased risks for breast, thyroid, uterine, colon, and renal cancers. BRRS is a disorder characterized by GI polyposis, macrocephaly, lipomas of the skin, and pigmented macules of the glans penis. PS is a disorder with variable expressivity, but often involving hamartomatous overgrowth of tissues, connective tissue nevi, epidermal nevi, and hyperostoses. The diagnosis of PHTS is made only when a PTEN pathogenic variant is identified. Inheritance is autosomal dominant.

Hereditary mixed polyposis syndrome (HMPS) is a rare condition described in only a few families worldwide. Individuals with HMPS are at an increased risk for adenomatous polyps, juvenile polyps, hyperplastic polyps, and polyps containing mixed histology. These individuals are also at increased risk for colon malignancy [Jaeger et al 2003]. HMPS1 (OMIM) is associated with a heterozygous duplication on chromosome 15q13-q14. HMPS2 (OMIM) is associated with a heterozygous pathogenic variant in BMPR1A. HMPS appears to be inherited in an autosomal dominant manner.

Serrated polyposis syndrome (SPS), previously referred to as hyperplastic polyposis syndrome, is characterized by sessile serrated polyps, serrated adenomas or hyperplastic polyps of the GI tract, and an increased risk of CRC. Criteria established by the WHO International Classification of Tumor Definition include (among others) the presence of 20 serrated (or hyperplastic) polyps distributed throughout the colon. Although the exact basis of SPS is debated, heterozygous germline pathogenic variants in PTEN, as well as biallelic germline pathogenic variants in MUTYH, have been found in a small number of individuals with SPS [Buchanan et al 2009, Kalady et al 2011].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with MUTYH -associated polyposis (MAP), the following evaluations are recommended:

  • Review of personal medical history with emphasis on those features related to MAP (or colorectal cancer): colon polyps with the majority being adenomas, colon cancer, rectal bleeding, abdominal pain and discomfort, bloating, diarrhea
  • Colonoscopy and review of pathology
  • Upper endoscopy and review of pathology
  • Baseline thyroid ultrasound examination at time of diagnosis as suggested by the Cleveland Clinic study [LaGuardia et al 2011]
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

In general, the treatment regarding gastrointestinal tumors is similar to that of familial adenomatous polyposis (FAP) and atypical familial adenomatous polyposis (AFAP) (see APC-Related Polyposis).

Colon polyps and colon cancer. Colonoscopy is effective surveillance for colon cancer; suspicious polyps should be removed (polypectomy) until polypectomy alone cannot manage the large size and density of the polyps. At that point either subtotal colectomy or proctocolectomy is performed based on polyp features and location [Lipton & Tomlinson 2006, Sampson & Jones 2009].

Duodenal polyps. Management of polyps is similar to individuals with FAP. In particular, large polyps or those polyps showing dysplasia or villous changes should be excised during endoscopy.

Abnormal thyroid findings should be evaluated by a thyroid specialist to determine what combination of monitoring, surgery, and/or fine needle aspiration (FNA) is appropriate [Cleveland Clinic study: LaGuardia et al 2011].

Surveillance

Individuals with Biallelic Germline MUTYH Pathogenic Variants

In the US-based National Comprehensive Cancer Network (NCCN) guidelines [NCCN 2012]:

  • Pan colonoscopy should be performed every one to two years beginning at age 25-30 years. Following surgery, endoscopy of any remaining colon or rectum should be performed every one to two years.
  • Upper endoscopy and side viewing duodenoscopy should be performed every three to five years beginning at age 30-35 years.
  • At this time there is no consensus regarding screening intervals for thyroid abnormalities [LaGuardia et al 2011].
  • Regarding extraintestinal malignancies, to date no specific surveillance beyond existing protocols that are offered to the general population in most Western countries is recommended.

In Europe:

  • Recommended ages at which screening should begin differ based on the consensus meeting in Mallorca [Vasen et al 2008] (full text; registration or institutional access required):
    • Pan colonoscopy beginning at age 18-20 years
    • Upper endoscopy with side viewing duodenoscopy beginning at age 25-30 years
  • Recommended intervals between screenings depend on disease severity [Spigelman et al 1989]

Individuals Heterozygous for a Germline MUTYH Pathogenic Variant

NCCN guidelines do not propose specific screening recommendations for individuals heterozygous for a germline MUTYH pathogenic variant.

Available data suggest that heterozygous relatives of individuals with MAP have a two- or at most threefold increase in their risk for colorectal cancer at an age similar to that in the general population (see Clinical Description, MUTYH heterozygotes). Thus, they are expected to benefit from population screening measures or could be offered average moderate-risk colorectal screening based on their family history [Jones et al 2009].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with genetically confirmed MAP by molecular genetic testing of the MUTYH pathogenic variants identified in the proband in order to reduce morbidity and mortality in those who would benefit from appropriate surveillance, early diagnosis, and treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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

MUTYH-associated polyposis (MAP) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband

  • Unless an individual with MAP has children with a carrier of a MUTYH pathogenic variant, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in MUTYH.
  • Since MUTYH pathogenic variants are present in 1%-2% of the population, children of individuals with one or two MUTYH pathogenic variants have a 0.5%-1.0% chance of inheriting two MUTYH pathogenic variants.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a MUTYH pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the MUTYH pathogenic variants in the family.

Reproductive partners of individuals with one or two MUTYH pathogenic variants can be offered MUTYH sequence analysis to determine MUTYH carrier status in order to clarify the risk for MAP in their offspring.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of asymptomatic individuals younger than age 18 years. Because screening and management does not begin prior to age 18 years in individuals with or at risk for MAP, genetic testing in individuals younger than age 18 years is not considered appropriate.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, 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) and molecular genetic testing when this has not been done before, to young adults who are affected, are carriers, or at risk of being carriers and to their reproductive partner to determine the risk of MAP in offspring (see Carrier Detection).

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 and Preimplantation Genetic Diagnosis

Once the MUTYH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MAP are possible.

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.

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.

  • Hereditary Colon Cancer Takes Guts
  • My46 Trait Profile
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • 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)
  • 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)
  • 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.

MUTYH-Associated Polyposis: Genes and Databases

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

Table B.

OMIM Entries for MUTYH-Associated Polyposis (View All in OMIM)

604933MutY, E. COLI, HOMOLOG OF; MUTYH
608456FAMILIAL ADENOMATOUS POLYPOSIS 2; FAP2

Gene structure. MUTYH, formerly known as MYH, has an open reading frame of 16 exons containing 1.9 kb. Older alternate names include hMYH, CYP2C, MGC4416, and RP4-534D1.

Multiple transcript variants encoding different isoforms have been found for this gene (www.ncbi.nlm.nih.gov/gene/4595). Following current HGVS recommendations, a coding DNA reference sequence was created from RefSeqGene record NG008189.1, transcript alpha 5, NM_001128425.1, for the description of sequence variants in MUTYH. Due to the choice of the longest MUTYH transcript (NM_001128425.1) as a reference, nucleotide and amino acid numbering after nucleotide position 157 (amino acid 53) may differ by up to 42 nucleotides (14 amino acids).

Pathogenic variants. Two common pathogenic variants, c.536A>G (p.Tyr179Cys) in exon 7 and c.1187G>A (p.Gly396Asp) in exon 13, are missense variants carried by approximately 1%-2% of the general population [Al-Tassan et al 2002, Cleary et al 2009]; they account for at least 90% of all MUTYH pathogenic variants in northern European populations. Nielsen et al [2009b] identified one or both of these founder pathogenic variants in up to 70% of persons with MAP. Note: To date these pathogenic variants have not been found in Koreans, Japanese, or Jewish persons of European origin, supporting the theory of founder pathogenic variants and ethnic differentiation [Miyaki et al 2005, Peterlongo et al 2006, Kim et al 2007, Yanaru-Fujisawa et al 2008].

Several other common, probable founder pathogenic variants have been reported in different populations (Reference sequences NM_001128425.1, NP_001121897.1):

Table 4.

Selected MUTYH Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.312C>Ap.Tyr104TerNM_001128425​.1
NP_001121897​.1
c.536A>Gp.Tyr179Cys
c.857G>Ap.Gly286Glu
c.1118C>Tp.Ala373Val
c.1187G>Ap.Gly396Asp
c.1214C>Tp.Pro405Leu
c.1227_1228dupGGp.Glu410GlyfsTer43
c.1437_1439delGGAp.Glu480del
c.1438G>Tp.Glu480Ter
Del exons 4-16 1

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 (varnomen​.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 MUTYH protein, adenine DNA glycosylase, plays a major role in DNA damage repair, specifically base excision repair, caused by ionizing radiation, various chemical oxidants, and reactive oxygen species generated during aerobic metabolism. In humans, the most mutagenic species from oxidative damage is 8-oxo7,8-dihydro2’deoxyguanosine (8-oxo-dG), which tends to mispair with adenine instead of the usual cytosine. This leads to G:C>T:A transversions in the DNA [Isidro et al 2004].

The key steps of DNA base excision repair are carried out by a set of enzymes that work together to prevent mutagenesis by 8-oxo-dG. The enzymes are nucleotide triphosphate NUDT1 (or MTH1) and DNA glycosylases OGG1 and MUTYH. NUDT1 prevents the oxidized G nucleotide from being incorporated during DNA replication by removing 8-oxodGTPs from the nucleotide pool and OGG1 detects and excises 8-oxo-dG adducts that have been misincorporated into the DNA. MUTYH recognizes and excises the misincorporated adenine bases to prevent the G:C>T:A transversion from occurring. After recognition of the mispaired 8-oxo-dG-A, MUTYH recruits the human checkpoint clamp Rad9–Rad1–Hus1 (9–1–1) complex for coordinating further enzymatic steps by assembling downstream proteins such as APE1, PCNA, polλ, and RPA1 repair the mutagenic abasic site [Parker & Eshleman 2003, Isidro et al 2004, Shi et al 2006, Luncsford et al 2013, Markkanen et al 2013].

Under oxidative stress, MUTYH functions as a molecular switch for programmed cell death thereby suppressing tumorigenesis [Markkanen et al 2013, Oka et al 2014]. In addition MUTYH is transcriptionally regulated by TP53 indicating that MUTYH is a potential mediator of p53 tumor suppression [Oka et al 2015].

Extensive alternative splicing of pre-mRNA, as well as use of alternate transcriptional start and polyadenylation sites results in several different isoforms of the MUTYH protein. There are three major MUTYH transcripts (α, β, and γ) that differ from each other in the 5′ end sequence [Ohtsubo et al 2000]. From these transcripts more than 15 transcripts are generated by alternative splicing at exon 1 and exon 3 [Oka & Nakabeppu 2011] and at least ten isoforms of the MUTYH protein (429-549 amino acids) [Out et al 2010, Markkanen et al 2013] (see www.ncbi.nlm.nih.gov/gene/4595).

The longest transcript variant, NM_001128425.1 (alpha 5) is being used as the coding DNA reference.

The isoforms differ in their N-terminus, which contains a mitochondrial localization signal (MLS). The putative nuclear localization signals (NLS) are located both at the N-terminus and C-terminus. The functional significance of the MLS and NLS in MUTYH is not entirely clear. The function of the alternative transcripts and isoforms is also still unclear [Markkanen et al 2013]. Possibly they possess different glycosylase activity levels and/or have different expression levels in different tissues [Ma et al 2004].

Abnormal gene product. A lack of functional MUTYH leads to accumulation of G:C>T:A transversions in daughter DNA strands post-replication. Studies indicate that this transversion is common in colorectal tumor DNA from individuals with MAP. These pathogenic variants result in the formation of a stop codon in the mRNA, which then results in a truncated protein product [Lipton & Tomlinson 2004].

Cancer

Somatic pathogenic variants in several cancer-related genes have been reported in MAP tumors [Nielsen et al 2009a]; however, KRAS pathogenic variants are most prevalent (found in 64% of colon cancers). KRAS (OMIM 190070) is involved primarily in regulating cell division and is a frequently activated oncogene in many different kinds of human tumors. KRAS activating variants cause Ras to accumulate in the active GTP-bound state by impairing intrinsic GTPase activity and conferring resistance to GTPase-activating proteins [Zenker et al 2007]. The critical regions of KRAS for oncogenic activation include codons 12, 13, 59, 61, and 63 [Grimmond et al 1992]. The reasons for predilection for the specific GGT>TGT transversion in codon 12 of KRAS in MAP colon cancers (and not another G>T transversion in codon 12 or another codon) are not yet understood.

Of note, somatic pathogenic variants in APC, which have been found in 14% to 83% of MAP-associated colon cancers [Nielsen et al 2009a], occur significantly more frequently in AGAA or TGAA motifs than in other motifs [Jones et al 2002]. Possible predilection for G>T transition in these specific sequences could reflect a higher susceptibility in these motifs for guanine oxidation or defective recognition and/or repair by mutated MUTYH [Jones et al 2002]; this remains to be clarified.

Furthermore, the high frequency of G>T transversions in KRAS (mutated in early tumor development) but not in TP53 and SMAD4 (implicated in tumor progression) could indicate a predominant MUTYH effect in early carcinogenesis [Nielsen et al 2009a].

References

Published Guidelines/Consensus Statements

  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Colorectal cancer screening. National Comprehensive Cancer Network, Inc. Available online. Registration required. 2012.
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Chapter Notes

Acknowledgments

The authors of this manuscript would like to thank Beth Dudley, MS, MPH, CGC for her assistance in editing and providing feedback about this GeneReview.

Revision History

  • 24 September 2015 (me) Comprehensive update posted live
  • 4 October 2012 (me) Review posted live
  • 21 June 2011 (ei) Original submission
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