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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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Hereditary Diffuse Gastric Cancer

Synonym: HDGC

, MSc, CCGC and , MD.

Author Information
, MSc, CCGC
Hereditary Cancer Program
BC Cancer Agency
Vancouver, British Columbia, Canada
, MD
Hereditary Cancer Program
BC Cancer Agency
Vancouver, British Columbia, Canada

Initial Posting: ; Last Update: June 21, 2011.

Summary

Disease characteristics. Hereditary diffuse gastric cancer (HDGC) is autosomal dominant susceptibility for diffuse gastric cancer, a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without forming a distinct mass. Diffuse gastric cancer is also referred to as signet ring carcinoma or isolated cell-type carcinoma. The average age of onset of HDGC is 38 years, with a range of 14-69 years. The majority of the cancers in individuals with a CDH1 mutation occur before age 40 years. The estimated cumulative risk of gastric cancer by age 80 years is 80% for both men and women. Women also have a 39%-52% risk for lobular breast cancer.

Diagnosis/testing. The International Gastric Cancer Linkage Consortium defined HDGC as the presence of two or more documented cases of diffuse gastric cancer in first- or second-degree relatives with at least one case diagnosed prior to age 50 years OR three or more documented cases of diffuse gastric cancer in first- or second-degree relatives, regardless of age of onset. CDH1 is currently the only gene in which mutations are known to cause hereditary diffuse gastric cancer.

Management. Treatment of manifestations: Ideally, management of individuals who have a CDH1 cancer-predisposing mutation is either intense surveillance for early detection and treatment of gastric cancer or prophylactic gastrectomy.

Surveillance: To date, the optimal management of individuals at risk for a cancer-predisposing mutation has been controversial because of the unproven value of surveillance regimes and the potential morbidity and mortality from prophylactic gastrectomy.

Genetic counseling. Hereditary diffuse gastric cancer is inherited in an autosomal dominant manner. The vast majority of individuals with a mutation predisposing to diffuse gastric cancer have inherited it from one parent. De novo mutations have not been reported. Each child of a proband has a 50% risk of inheriting the cancer-predisposing mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known; however, requests for prenatal testing for conditions which (like HDGC) do not affect intellect and have some treatment available are not common.

Diagnosis

Clinical Diagnosis

Criteria for consideration of CDH1 molecular genetic testing in individuals with diffuse gastric cancer (DGC) were revised in 2005 when a new cohort of families with hereditary DGC was tested [Suriano et al 2005]. These current criteria are applicable to North America, northern Europe, and other regions of low gastric cancer incidence but are likely too broad for use in regions of high gastric cancer incidence such as Japan and Korea.

Modified testing criteria

  • Family with two or more cases of gastric cancer (GC), with at least one DGC diagnosed before age 50 years. (>30%)
  • Family with multiple lobular breast cancer (LBC) with or without DGC in first- or second-degree relatives (unknown)
  • Single individual from a low-incidence population (<10%) diagnosed with DGC before age 35 years
  • An individual with both DGC and LBC (unknown)

Potential additional criteria

  • Family with three or more cases of GC diagnosed at any age, one or more of which is documented to be DGC; no other criteria met (such families are extremely rare)
  • Family with one or more cases of both DGC and signet ring colon cancer (this association is unproven)

The International Gastric Cancer Linkage Consortium (IGCLC) recently redefined the clinical criteria in consensus guidelines [Fitzgerald et al 2010; see Image guidelines.jpg for full text] as follows:

  • Two gastric cancer (GC) cases in family, one individual under age 50 years with confirmed diffuse gastric cancer (DGC)
  • Three confirmed DGC cases in first- or second-degree relatives independent of age
  • Simplex case (i.e., a single occurrence in a family) of DGC occurring before age 40 years
  • Personal or family history of DGC and lobular breast cancer, one diagnosed before age 50 years

Molecular Genetic Testing

Gene. CDH1, encoding the protein E-cadherin, is the only gene in which mutations are known to be associated with HDGC [Gayther et al 1998, Guilford et al 1998, Richards et al 1999, Yoon et al 1999, Dussaulx-Garin et al 2001, Humar et al 2002, Oliveira et al 2002, Jonsson et al 2002, Brooks-Wilson et al 2004, Keller et al 2004, Suriano et al 2005, Frebourg et al 2006, Rodriguez-Sanjuan et al 2006, Kaurah et al 2007, Masciari et al 2007, More et al 2007, Roviello et al 2007, Van Domselaar et al 2007, Oliveira et al 2009, Ghaffari et al 2010, Mayrbaeurl et al 2010].

Evidence for possible locus heterogeneity. Mutations in CDH1 account for approximately 30%-50% of HDGC in North American families with HDGC [Kaurah et al 2007].

Since between 50%-70% of families with HDGC reported to date have no identifiable CDH1 germline mutation, it is likely that some of these families may have mutations in other unidentified HDGC-susceptibility genes. Although the candidate genes have been analyzed, no mutations have been found to date in any of them. Candidate genes considered and excluded include:

Clinical testing

  • Sequence analysis. Bidirectional sequence analysis of all coding portions and intron-exon boundaries of CDH1 detects mutations in about 30%-50% of individuals with a clinical diagnosis of HDGC [Oliveira et al 2006, Kaurah et al 2007]. This technique detects mutations that include single base substitutions as well as small deletions and insertions.
  • Deletion/duplication analysis. Deletion/duplication analysis identifies exonic or whole-gene deletions in:

Table 1. Summary of Molecular Genetic Testing Used in Hereditary Diffuse Gastric Cancer

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
CDH1Sequence analysisSequence variants 230%-50%
Deletion / duplication analysis 3Exonic or whole-gene deletions4% 4

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

4. All persons with HDGC

Interpretation of test results

  • Truncating mutations are assumed to be pathogenic.
  • For issues to consider in interpretation of sequence analysis results, click here.

Note: Clinical management in individuals with missense mutations remains problematic because both extensive family data and functional data are needed in order to predict the pathogenicity of a missense mutation. In the absence of such data, it may not be appropriate to use CDH1 missense mutation to define risks.

Testing Strategy

To confirm/establish the diagnosis in a proband suspected of having gastric cancer, the following consensus guidelines have been developed by the IGCLC [Fitzgerald et al 2010, Figure 1; see Image guidelines.jpg for full text].

  • A complete personal medical history
  • A three-generation family history to determine if diffuse gastric cancer, lobular breast, and/or signet ring cell colon cancer is present in the family
  • Endoscopic biopsy to confirm the diagnosis of diffuse gastric cancer or precursor lesions in one family member
  • Sequence analysis of CDH1, followed by deletion/duplication analysis if a mutation is not identified, to determine if a germline CDH1 mutation is present in a family member with diffuse gastric cancer and/or lobular breast cancer

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Age of onset. The average age of onset of hereditary diffuse gastric cancer (HDGC) is 38 years, with a range of 14 to 69 years. The majority of the gastric cancers occur before age 40 years. The age of onset is also variable between and within families [Gayther et al 1998, Guilford et al 1998]. The lifetime risk for diffuse gastric cancer in males and females heterozygous for a CDH1 germline mutation is 80% [Paul Pharoah, unpublished data].

Symptoms. Symptoms are nonspecific in the early stages of the disease. Consequently, when present, nonspecific symptoms tend to be dismissed both by affected individuals and by physicians. By the time symptoms appear, affected individuals are in an advanced stage of the disease [Wanebo et al 1993]. Symptoms in the late stage may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. Late in the course of stomach cancer, a palpable mass may be present.

Tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures.

Other cancers. Other cancers reported in family members include:

Survival. When sporadic (i.e., non-hereditary) diffuse gastric cancer is detected early, i.e., before it has invaded the wall of the stomach, the five-year survival rate can be greater than 90%. The five-year survival rate drops to lower than 20% when the diagnosis is made at a late stage [Karpeh et al 2001].

Because early detection of DGC is difficult, survival of individuals with CDH1 mutations is believed to be the same as in individuals with sporadic DGC.

Pathology. In DGC, loss of the E-cadherin protein causes the individual tumor cells to grow and invade neighboring structures. The individual malignant cells infiltrate and spread under histologically normal-looking mucosa causing widespread thickening and rigidity of the gastric wall, a phenomenon known as linitis plastica [McColl 2006]. No tumor mass is formed, unlike that of the intestinal type. The malignant cells have a distinctive signet ring appearance which is caused by an accumulation of intracellular mucin that pushes the nucleus to one side. There is no known premalignant lesion for DGC.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been reported to date.

Penetrance

The penetrance of HDGC is incomplete. Based on data from 11 families, Pharoah et al [2001] estimated the cumulative risk for gastric cancer by age 80 years to be 67% for men (95% confidence interval, 39-99 years) and 83% for women (95% confidence interval, 58-99 years). Revised penetrance data reveal that the lifetime risk for diffuse gastric cancer in both male and female CDH1 heterozygotes is 80% [Paul Pharoah 2008, unpublished data].

Females heterozygous for a CDH1 mutation have a 39%-52% risk for LBC [Pharoah et al 2001, Kaurah et al 2007].

In four families (including one large family with >300 individuals) with the CDH1 2398delC mutation [Kaurah et al 2007]:

  • The cumulative risk of gastric cancer by age 75 years was estimated at 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females.
  • The cumulative risk for breast cancer for females by age 75 years was 52% (95% CI, 29%-94%).

Anticipation

No reports in the literature provide evidence for anticipation in this syndrome.

Prevalence

Worldwide, the cancer burden of gastric cancer is second only to lung cancer [Parkin et al 2001]. Stomach cancer incidence rates show substantial variation internationally [Parkin et al 2001]. Rates are highest in Japan (80 cases per 100,000) and eastern Asia. Other areas of the world with high incidence of stomach cancer include Eastern Europe and parts of Latin America. Incidence rates are generally lower in Western Europe and the United States (10-40:100,000).

Although the incidence of gastric cancer is higher in Japan and China, most of the CDH1 mutations have been found in European populations. There is, however, the possibility of a higher incidence of HDGC in New Zealand Maori families [Humar et al 2002].

Differential Diagnosis

Intestinal-Type Gastric Cancer (IGC) vs Diffuse Gastric Cancer (DGC)

About 5%-10% of all gastric cancer is thought to be familial [Zanghieri et al 1990, La Vecchia et al 1992]. Familial gastric cancer is both clinically and genetically heterogenous.

The characteristic morphologic difference between the two variants results from either the presence or lack of a key intercellular adhesion molecule, E-cadherin. There is loss of expression of the E-cadherin protein in the diffuse type, whereas it tends to be well preserved in the intestinal type. Consequently, IGC, the more common of the two variants [Crew & Neugut 2006] is composed of tubular or glandular formations of variable differentiation that resemble adenocarcinomas of the intestinal tract [Lynch et al 2005]. IGC arises from a precursor lesion, intestinal metaplasia; it forms a large protruded, ulcerated, or infiltrative lesion in the stomach.

IGC:

  • Is the more common of the two [Crew & Neugut 2006];
  • Tends to occur more frequently in men than in women;
  • Increases significantly with age;
  • Shows marked geographic variation with the highest rates found in China, South Korea, Japan, Eastern Europe, and South America and the lowest rates occurring in North America, Northern and Western Europe, Northern and Western Africa, and Southeast Asia;
  • Appears to be sporadic and is related to environmental factors. The most well-recognized environmental risk factor for GC is chronic gastric mucosal infection with Helicobacter pylori leading to a chronic atrophic gastritis [Uemura et al 2001, Suerbaum & Michetti 2002]. This led to the bacterium being declared as a class one carcinogen by the International Agency for Research on Cancer and the World Health Organization in 1994. Although approximately two thirds of the world’s population (primarily in developing countries) is infected with the H. pylori, only a small proportion develop GC.

The risk to an infected individual of developing IGC depends on the following three factors:

  • Genetic features of the bacterial strain. Tiwari et al [2008] showed that young individuals infected with H. pylori with the genotype cagT+ve/hrgA+ve/cagA+ve/cagE+ve/vacAs1+ve have an increased risk for cancer. In a follow-up study, Tiwari et al [2010] revealed a closer relationship between the genotypes of the H. pylori, plasma malondialdehyde levels, and nitric oxide levels and gastric histopathology. Other studies have shown that cagA is associated with a 20-fold greater risk of GC than controls [Malfertheiner et al 2005].
  • Genetic features of the host. Certain sequence variants in the genes that constitute the interleukin-1 gene cluster − TNF (the gene encoding tumor necrosis-α) and IFNGR1 (the gene encoding interferon gamma receptor 1) − significantly increase the risk for gastric cancer, particularly in those infected with virulent strains of the bacterium [El-Omar et al 2001, El-Omar et al 2003, Rad et al 2003, Canedo et al 2008]. The bacterial and host genetic factors contribute to the progression of gastritis to chronic atrophic gastritis, to intestinal metaplasia, and finally to GC.
  • Environment. In Colombia, intervention studies with antioxidant supplements have shown that vitamin C and β-carotene, as well as H. pylori eradication therapy, produced significant regression of gastric precancerous lesions, atrophy, and intestinal metaplasia in the stomach. This study concluded that continual supplements are required to maintain protection, as the benefits of antioxidants were no longer evident after six years [Correa et al 2000]. The improving hygiene in developed countries has also contributed to the decline of infection and therefore H. pylori-associated cancer [Roosendaal et al 1997].

    Additional environmental factors including smoking and diets high in nitrites, salt, and smoked or pickled foods and low in fruit and vegetables are believed to increase the risk of GC [Forman & Burley 2006, van den Brandt & Goldbohm 2006, Liu & Russell 2008, González & López-Carrillo 2010].

Diffuse-type gastric cancer does not appear to be declining in incidence nor does it show marked geographic variation. Although the underlying causes are unknown, it may actually be increasing in incidence in North America [Borch et al 2000].

H. pylori infection poses a similar risk for DGC as for IGC [Lynch et al 2005, Kamangar et al 2006], although DGC is not linked to a precursor lesion.

Genetic features of the bacterial strain. There is evidence to support epigenetic effects of H. pylori infection where promoter hypermethylation of CDH1 in normal infected gastric mucosa was reversible with antibiotic treatment of the bacteria [Perri et al 2007]. Apart from the two of 17 prophylactic gastrectomy specimens reported by Blair et al [2006] that had previous H. pylori infection on serologic testing, there no evidence of increased rates of H. pylori infection associated with the microscopic DGCs in the prophylactic gastrectomy specimens of heterozygotes for a CDH1 disease-causing mutation.

Other Cancer Predisposition Syndromes

Gastric cancer is seen in several other cancer predisposition syndromes, including Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) [Aarnio et al 1997], Li-Fraumeni syndrome (LFS) [Varley et al 1995], familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome [Williams et al 1982], and Cowden syndrome, one of the PTEN hamartoma tumor syndrome phenotypes [Hamby et al 1995].

Lynch syndrome. Lynch syndrome, which is associated with germline mutations in mismatch repair genes, predisposes heterozygotes to colorectal and other cancers. Gastric cancer is the third most common cancer in these individuals. IGC is the predominant subtype in Lynch syndrome [Lynch et al 2005].

Microsatellite instability (MSI) was observed in approximately 15% of gastric cancers from individuals in Florence, Italy, an area with high gastric cancer risk [D’Errico et al 2009]. Gastric cancers with high MSI tend to occur in the antrum of the stomach, be of the intestinal type, and have better survival rates [Leung et al 1999, Wu et al 2000, Falchetti et al 2008].

Familial adenomatous polyposis (FAP). FAP is caused by germline mutations in APC. Gastric cancer has been seen in 0.6% of persons with FAP [Jagelman et al 1988].

Li-Fraumeni syndrome (LFS). Cancers in LFS are caused by mutations in either TP53 or CHEK2. Both DGC and IGC are observed [Keller et al 2004, Oliveira et al 2004].

BRCA1 and BRCA2 hereditary breast and ovarian cancer. Increased risk of GC has been associated with mutations in BRCA1 [Brose et al 2002, Friedenson 2005] and BRCA2 [Breast Cancer Linkage Consortium 1999, Risch et al 2001].

  • Gastric cancer occurs in 5.7% of families with the BRCA2 6174delT mutation [Figer et al 2001].
  • Jakubowska et al [2002] found that in a subset (7%) of individuals with gastric cancer, a BRCA2 mutation may be the underlying genetic cause; however, the histopathology of the gastric cancer was not reported. Because the individuals with gastric cancer were deceased, they could not be tested for the mutations found in their families. There have been no updates regarding the latter study.

Carney complex. A rare gastric lesion, gastric leiomyosarcoma, is found in individuals with Carney complex [Carney et al 1977].

Carney-Stratakis syndrome (CSS). Gastric stromal sarcomas were observed in 12 individuals with this disorder who had paraganglioma, gastric stromal sarcoma, or both [Carney & Stratakis 2002]. Germline mutations in SDHB, SDHC, and SDHD are causative [Pasini et al 2008]. Inheritance is autosomal dominant.

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

The IGCLC has updated consensus guidelines for clinical management of individuals with a CDH1 mutation [Fitzgerald et al 2010; see Image guidelines.jpg for full text].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with hereditary diffuse gastric cancer, the following evaluations are recommended:

  • Baseline endoscopy to look for macroscopic tumor [Fitzgerald et al 2010]
  • Evaluation of CDH1 heterozygotes for H. pylori infection given its ability to induce promoter hypermethylation of CDH1 and its role in GC carcinogenesis
  • Breast examination/mammography in females

Treatment of Manifestations

Care by a multidisciplinary team comprising those with expertise in medical genetics, gastric surgery, gastroenterology, pathology, and nutrition is recommended [Fitzgerald et al 2010, Figure 1; see Image guidelines.jpg for full text].

Treatment as indicated for H. pylori infection.

The primary curative treatment of gastric cancer is surgical resection. Regardless of the surgical procedure used for the treatment of gastric cancer, the effectiveness of surgical resection is poor if the ultimate goal is increased cure rate. Studies have shown that surgery alone is less than satisfactory in the management of early gastric cancer, with cure rates approaching only 40%. The role of adjuvant therapy was indefinite until three large, randomized controlled trials showed the survival benefit of adjuvant therapy over surgery alone [MacDonald et al 2000, Cunningham et al 2006, Sakuramoto et al 2007].

Numerous randomized clinical trials have failed to show consistent survival benefits from adjuvant radiation therapy or chemotherapy alone in the treatment of gastric cancer.

Prevention of Primary Manifestations

Biopsy-proven diffuse-type gastric carcinoma. Prophylactic total gastrectomy is recommended if a biopsy shows diffuse-type gastric carcinoma [Chun et al 2001, Fitzgerald et al 2010].

Heterozygotes for a germline CDH1 mutation. The importance of identifying the genetic basis of cancer susceptibility in families with HDGC has been underscored by the observation of early gastric cancers in prophylactic total gastrectomy (PTG) samples obtained from individuals with a germline CDH1 mutation [Chun et al 2001, Huntsman et al 2001, Norton et al 2007]. These findings suggest that currently prophylactic total gastrectomy, rather than endoscopic surveillance, is the best preventive measure for individuals who have a CDH1 germline mutation.

Prophylactic total gastrectomy (PTG). PTG involves D-2 dissection and Roux-en-Y esophagojejunostomy and obtaining proximal margins to ensure removal of the gastric mucosa [Norton et al 2007].

In a young, healthy individual, the risk of mortality with PTG in an experienced surgeon’s hands is less than 1% [Lynch et al 2005]. However, the morbidity from prophylactic gastrectomy is high. All individuals have long-term morbidity related to both immediate postsurgical complications as well as long-term complications. Long-term complications include rapid intestinal transit, dumping syndrome, diarrhea, eating habit alterations, and weight loss [Caldas et al 1999, Lewis et al 2001]. In addition, the risk for malabsorption increases after total gastrectomy; malabsorption accounts for the increased incidence of osteoporosis, osteomalacia, and malnutrition described in persons with gastric cancer [Liedman 1999].

In light of these possible complications, it is recommended that a multidisciplinary team including a surgeon, gastroenterologist, and dietician provide pre-operative and post-operative care for an individual undergoing PTG. The multidisciplinary team members can counsel candidates for PTG on the risks and benefits of the surgery. In making the decision to undergo PTG, the affected individual and his/her physicians should consider:

  • The age-specific risks of gastric cancer. Due to nutritional implications, PTG is not generally recommended until the individual’s growth period is complete. In families in which gastric cancer is early onset, PTG should be considered on a case by case basis [Blair et al 2006]. In these individuals, regular endoscopic screening may be begun prior to the consideration of PTG.
  • The 100% morbidity of gastrectomy and the 1% risk of mortality following the surgery
  • The risk in individuals with a CDH1 mutation of developing extragastric cancers, such as lobular breast cancer and colorectal cancer, and the screening recommendations for these cancers

Breast Cancer

Referral to a high risk breast clinic is recommended [Fitzgerald et al 2010].

Prophylactic mastectomy may be considered in women heterozygous for a CDH1 germline mutation. The authors are aware of only a handful of women who have to date undergone prophylactic mastectomy for this reason. It is important to note that prophylactic mastectomy can have psychological effects so appropriate counseling should include the possible altered perception of the body and sexual relationships [Brandberg et al 2008, Lodder et al 2002].

Surveillance

Gastric Cancer

Although it has been proposed that individuals who have a CDH1 germline mutation undergo routine surveillance for gastric cancer, the optimal management of individuals at risk for a gastric cancer is controversial because of the unproven value of surveillance regimes. In most cases, the gastric cancer is not detected until it reaches an incurable, advanced stage. Samples obtained at the time of prophylactic gastrectomy of six asymptomatic individuals with a CDH1 germline mutation revealed occult disease on microscopic analysis even though each individual had had normal screening tests prior to surgery [Norton et al 2007].

Due to the highly penetrant nature of HDGC caused by a germline CDH1 mutation, it is recommended that at-risk individuals who are not ready to undergo PTG or who have declined it be screened every 6-12 months by upper endoscopy with multiple random biopsies [Norton et al 2007, Barber et al 2008, Fitzgerald et al 2010 (see Image guidelines.jpg for full text)]. Screening should begin 5-10 years prior to the earliest cancer diagnosis in the family.

Several screening modalities have been tested:

Endoscopy. The effectiveness of endoscopy (currently the only method in use) in detecting the early lesions of gastric cancer has not been proven. Endoscopy permits direct inspection and biopsy of suspicious areas, but diffuse gastric cancer is difficult to detect at an early, treatable stage because the lesions tend to spread in the submucosa rather than as exophytic masses. The problems are: (1) difficulty in identifying the submucosal lesions and (2) sampling bias in a macroscopically normal-appearing gastric mucosa [Fitzgerald & Caldas 2004, Norton et al 2007]. It is recommended that individuals at risk who do not wish to have prophylactic gastrectomy undergo a detailed 30-minute endoscopic examination of the gastric mucosa with multiple random biopsies and biopsies of subtle lesions at six- to 12-month intervals [Caldas et al 1999].

Chromoendoscopy, using indigo-carmine staining, has been shown to improve the detection rate of early gastric cancer [Stepp et al 1998, Fennerty 1999]. Charlton et al [2004] studied six stomachs removed prophylactically after macroscopically normal gastric endoscopies. A pH-sensitive congo red dye followed by pentagastric stimulation revealed signet ring foci that were five times more prevalent in the transitional zone of the distal stomach, a finding in contrast with other studies [Carneiro et al 2004]. The transitional zone occupies less than 10% of the stomach and lacks gastric-secreting G cells. The authors suggest that chromoendoscopy using congo red dye and pentagastric stimulation may highlight this area during endoscopy and thus increase the chances of detecting cancer foci. Further research is needed to evaluate this possibility.

The same group of investigators reported a year later on a follow-up of 99 surveillance endoscopies over five years [Shaw et al 2005]:

  • 69 of 99 (70%) endoscopies were normal
  • 23 lesions with signet ring cell cancer were identified in ten individuals
  • The congo red/methylene blue dye detected foci between 4-10mm, not less than 4 mm.

These findings need to be evaluated in larger group of CDH1 germline mutation heterozygotes. However, concerns over the toxicity of congo red have precluded the use of this stain in chromoendoscopy.

Endoscopic ultrasound examination is important in the detection and staging of gastrointestinal cancers [Pfau & Chak 2002], but is not believed to be useful in detecting precursor lesions [Fitzgerald & Caldas 2004].

Other. Several other tools utilized include PET scan [van Kouwen et al 2004], endoscopic ultrasound, stool for guaiac, abdominal CT, and multiple random stomach biopsies [Barber et al 2008]. Unfortunately none of these reliably detects DGC, as demonstrated by the finding of multiple small cancer foci in six of six gastrectomy specimens from CDH1 mutation heterozygotes a week after a number of these screening investigations were done [Norton et al 2007].

Lobular Breast Cancer (LBC)

Currently the data on women with germline CDH1 mutations and development of lobular breast cancer are insufficient to determine the best cancer screening strategies. Recommendations for LBC risk management in CDH1 heterozygotes or at-risk women are based on recommendations for women with a BRCA1 or BRCA2 germline mutation (see BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. At-risk women should undergo regular breast screening as determined by their physicians, including monthly breast self-examinations and a clinical breast examination every six months.

  • Because lobular breast cancer is often difficult to diagnose on clinical examination and mammography, it may also be prudent to refer a woman who has a CDH1 germline mutation to a high-risk breast cancer screening program and to consider use of MRI, which appears to be more sensitive than mammography in detecting tumors in such women [Schelfout et al 2004; Schelfout, personal communication].
  • The screening should begin by age 35 years or 5-10 years prior to the youngest age of breast cancer diagnosis in the family [Fitzgerald et al 2010].

Colon Cancer

Although evidence is insufficient to conclude that colon cancer is a manifestation of HDGC, it is prudent to recommend colonoscopy every three to five years beginning at age 40 years or ten years prior to the youngest age of colon cancer diagnosis in families in which both DGC and colon cancer have occurred [Fitzgerald et al 2010].

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk relatives if the CDH1 disease-causing mutation is identified in an affected family member, so that morbidity and mortality can be reduced by early diagnosis and treatment. See Genetic Counseling, Testing of asymptomatic at-risk individuals younger than age 18 years for discussion of issues related to testing of this population.

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

Testing of Populations at Risk

In Japan, where the prevalence of gastric cancer is high, a mass population screening program allows for successful detection of early disease by endoscopy [Shiratori et al 1985]. In this program, all suspicious findings seen on endoscopy are biopsied and evaluated histologically. Suspicious findings include minute changes in the color of the mucosa, altered vascular pattern, roughened surface, flat lesions, and minor mucosal irregularities.

Pregnancy Management

Evidence shows that pregnancy after PTG can have healthy and normal outcomes. Kaurah et al [2010] discussed six healthy pregnancies and infants born to four women after total gastrectomy.

Therapies Under Investigation

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

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

Hereditary diffuse gastric cancer is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The majority of individuals with a CDH1 mutation predisposing to diffuse gastric cancer have inherited it from one parent. It is possible that the parent from whom the mutation was inherited may not have developed cancer because of incomplete penetrance.
  • In addition, a proband with HDGC may have the disorder as the result of a de novo mutation; however, a de novo mutation has not been reported in an individual with HDGC and is probably rare.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing.

Note: Although most individuals diagnosed with HDGC 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 incomplete penetrance.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected and/or has a CDH1 mutation, the risk to the sibs of inheriting the mutation is 50%.
  • If the disease-causing mutation cannot be detected in the DNA of either parent and biparental inheritance at the CDH1 locus is proven by haplotype inheritance, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. The risk to the sibs of the proband depends on the spontaneous mutation rate of CDH1 and the probability of germline mosaicism in a parent. No instances of de novo mutations or germline mosaicism have been reported, although these remain possibilities.

Offspring of a proband. Each child of a proband has a 50% risk of inheriting the cancer-predisposing mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a CDH1 mutation, his or her family members are at risk.

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.

Genetic cancer risk assessment and counseling. For comprehensive descriptions 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)

Testing of asymptomatic at-risk adults. Testing of asymptomatic at-risk adults for HDGC is possible only after an affected family member has been tested and a CDH1 disease-causing mutation found. Testing of an asymptomatic at-risk individual is considered predictive testing, not diagnostic testing. Lynch et al [2000] describe the genetic counseling process that they followed with a large kindred with HDGC. Relevant issues that should be discussed with family members seeking predictive testing for HDGC include:

  • The genetics of cancer development and HDGC
  • The individual's knowledge of HDGC
  • The individual's reasons for requesting the test
  • The individual's understanding of the risk for having inherited the mutation based on family history of HDGC
  • Availability of molecular genetic testing
  • Cancer risk if the individual has inherited the mutation
  • Recommendations for cancer screening and prophylactic surgery
  • The possible social impact of positive and negative test results

In 50%-70% of families with HDGC, cancer susceptibility is caused by unknown genetic factors; thus predictive testing is not possible at present.

Testing of asymptomatic at-risk individuals younger than age 18 years. Genetic testing in individuals younger than age 18 years has always been a controversial issue. Since there have been reports of individuals younger than age 18 years who are diagnosed with HDGC [Guilford et al 1998], it has been suggested that genetic testing in individuals younger than age 18 years may be beneficial [Caldas et al 1999, Fitzgerald et al 2010]. Kodish [1999] proposed the application of the following rule to the testing of minors: genetic testing should be permitted at an age no earlier than the age of first possible onset of cancer. He states that this rule tries to maximize the benefits to the child while minimizing the risks. Overall, a request from parents for testing of asymptomatic at-risk individuals younger than age 18 years requires sensitive and understanding (though rigorous) counseling for both the parents and child. The IGCLC has agreed that genetic testing of at-risk individuals at age 16 years can be considered if the age of onset in the family is early [Fitzgerald et al 2010].

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk of inheriting a CDH1 mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at about ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like HDGC) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and in 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) may be an option for some families in which the disease-causing mutation has been identified.

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.

  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • No Stomach For Cancer, Inc.
    9202 Waterside Street
    #203
    Middleton WI 53562
    Phone: 608-335-0241
    Email: info@nostomachforcancer.org
  • PMP Pals
    PO Box 6484
    Salinas CA 93912
    Phone: 831-424-4545
    Email: pmppals@yahoo.com
  • AMC Cancer Fund/Research Center
    1600 Pierce Street
    Denver CO 80214
    Phone: 800-321-1577 (toll-free); 303-233-6501
    Fax: 303-239-3400
    Email: contactus@amc.org
  • 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)
  • CancerCare
    275 Seventh Avenue
    Floor 22
    New York NY 10001
    Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
    Fax: 212-712-8495
    Email: info@cancercare.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. Hereditary Diffuse Gastric Cancer: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CDH116q22​.1Epithelial cadherinCDH1 @ LOVDCDH1

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 Hereditary Diffuse Gastric Cancer (View All in OMIM)

137215GASTRIC CANCER, HEREDITARY DIFFUSE; HDGC
192090CADHERIN 1; CDH1

Molecular Genetic Pathogenesis

E-cadherin is a transmembrane protein that is predominantly expressed at the basolateral membrane of epithelial cells where it exerts cell–cell adhesion and invasion suppression functions [Nagar et al 1996].

E-cadherin is one member of the cadherin family of molecules, all of which are transmembrane glycoproteins mediating calcium-dependent cell-cell adhesion [Takeichi 1991, Berx et al 1995]. E-cadherin is critical for establishing and maintaining polarized and differentiated epithelia during development [Keller 2002]. It also plays important roles in signal transduction, differentiation, gene expression, cell motility, and inflammation. The activity of E-cadherin in cell adhesion is dependent upon its association with the actin cytoskeleton via undercoat proteins called catenins (α-, β-, and γ-) [Jou et al 1995, Kallakury et al 2001].

A role for E-cadherin in tumor development is well established [Wijnhoven et al 2000] because many human carcinomas, for example, skin, lung, breast, urological, gastric, colon, pancreatic, and ovarian, exhibit reduced E-cadherin expression relative to their normal cellular counterparts [Karayiannakis et al 2001, Tsanou et al 2008, Ch’ng & Tan 2009, Kuner et al 2009, Giroldi et al 2000]. Loss of E-cadherin expression is seen in most diffuse gastric cancers and in lobular breast cancers; expression is usually maintained in intestinal gastric cancers and ductal breast cancers [Hirohashi 2000].

Cells deficient in E-cadherin lose their ability to adhere to each other and consequently become invasive and metastasize [Birchmeier 1995, Perl et al 1998]. The causal effect of E-cadherin loss or dysregulation in tumorigenesis has been demonstrated using carcinoma cell lines and transgenic models [Hsu et al 2000]. This loss of E-cadherin expression has been shown to be an early event through the examination of in situ DGC lesions from a prophylactic total gastrectomy specimen. This loss of E-cadherin reveals that it is an early initialing event that leads to invasion [Humar et al 2007].

Loss of heterozygosity is a common phenomenon seen in association with loss of expression of tumor suppressor genes [Knudson 1971]. The tumor suppressor function of E-cadherin is supported through evidence of the loss of expression of the other CDH1 allele [Grady et al 2000, Barber et al 2008, Oliveira et al 2009].

Normal allelic variants. CDH1 comprises 16 exons that span 100 kb.

Pathologic allelic variants. To date, over 100 germline mutations have been reported in families with HDGC [Guilford et al 1998, Gayther et al 1998, Yoon et al 1999, Richards et al 1999, Dussaulx-Garin et al 2001, Humar et al 2002, Oliveira et al 2002, Jonsson et al 2002, Brooks-Wilson et al 2004, Keller et al 2004, Suriano et al 2005, Frebourg et al 2006, Rodriguez-Sanjuan et al 2006, Kaurah et al 2007, Masciari et al 2007, More et al 2007, Roviello et al 2007, Van Domselaar et al 2007, Oliveira et al 2009, Mayrbaeurl et al 2010, Ghaffari et al 2010].

The mutations have mainly been truncating mutations, usually through frameshift mutations, exon/intron splice site mutations, or point mutations [Gayther et al 1998, Guilford et al 1998, Richards et al 1999, Oliveira et al 2002, Humar et al 2002, Brooks-Wilson et al 2004].

Missense mutations have also been identified in some families [Shinmura et al 1999, Yoon et al 1999, Oliveira et al 2002, Brooks-Wilson et al 2004]. The pathogenicity of missense mutations can be determined through in vitro analysis [Suriano et al 2003].

Large exonic deletions make up approximately 5% of these mutations [Oliveira et al 2009].

No "hot spots" have been identified; the mutations have been scattered throughout the gene. However, there are reports of the same mutation being found in several unrelated families:

A founder mutation has been seen in four families from Newfoundland, Canada [Kaurah et al 2007]. The mutation, 2398delC was confirmed by haplotype analysis in these families.

Germline mutations have been identified in several ethnic groups; germline mutations appear to be rare in countries in which the rates of sporadic GC are high. The reason is not known; it may be postulated that the differences in genetic backgrounds of the various ethnicities may have different effects on the viability of embryos that already have one mutated germline CDH1 allele.

Normal gene product. The 4.5-kb transcript is translated into a 135-kd precursor polypeptide of E-cadherin. This in turn is rapidly processed to the mature 120-kd form. The mature E-cadherin protein contains three domains: the extracellular domain encoded by exons 4-13, the transmembrane domain encoded by parts of exons 13 and 14, and the highly conserved cytoplasmic domain encoded by the rest of exon 14 to exon 16.

  • The large extracellular domain (N-terminal) is made up of five tandem cadherin repeats each containing about 110 amino acid residues [Oliveira 2003, Bryant & Stow 2004]. The extracellular domain homodimerizes with E-cadherin expressed in neighboring epithelial cells in a Ca2+-dependent manner thus enabling cell-cell adhesion at the zonula adherens junctions of the homotypic neighboring cells.
  • The cytoplasmic domain (C-terminal) interacts with the cytoskeleton actin filaments through α-, β-, and γ-catenins and p120ctn catenins in regulating the intracellular signaling pathways. β-catenin attaches to the C-terminal region of E-cadherin and then to α-catenin, which then binds to the F-actin microfilaments of the cytoskeleton. p120ctn binds to a juxtamembrane site of E-cadherin cytoplasmic tail [Bryant & Stow 2004]. p120 also provides complex stability [Weis & Nelson 2006].

E-cadherin expression is controlled through a complex transcriptional regulation system.

  • Several transcriptional repressors such as Snail, Slug, Twist, Sip-1/ZEB-2, dEF1/ZEB-1, and E12/E47 bind to the E-box motifs in the CDH1 promoter [Conacci-Sorrell et al 2003, Nelson & Nusse 2004, Gloushankova 2008].
  • Intron 2 of CDH1 has been implicated in the normal expression of the gene. Intron 2, which accounts for the majority of the non-coding intronic sequences of CDH1, contains conserved cis-regulatory elements. Stemmler et al [2005] performed a study in which deletion of murine genomic intron 2 led to inactivation of the gene during early embryonic development.

Abnormal gene product. See Molecular Genetic Pathogenesis.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. Fitzgerald RC, Hardwick R, Huntsman D, Carneiro F, Guilford P, Blair V, Chung DC, Norton J, Ragunath K, Van Krieken JH, Dwerryhouse S, Caldas C; International Gastric Cancer Linkage Consortium. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. 2010. Available online. Accessed 6-13-11. [PMC free article: PMC2991043] [PubMed: 20591882]
  2. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K. American Society of Clinical Oncology; American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. 2010. Available online (registration or institutional access required). Accessed 6-13-11.

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Suggested Reading

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Chapter Notes

Revision History

  • 21 June 2011 (me) Comprehensive update posted live
  • 31 August 2006 (pk) Revision: prenatal diagnosis clinically available
  • 13 December 2004 (me) Comprehensive update posted to live Web site
  • 4 November 2002 (me) Review posted to live Web site
  • 5 April 2002 (pk) Original submission
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    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

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