Genetics of Gastric Cancer (PDQ®): Genetics - Health Professional Information [NCI]

Introduction

Gastric cancer is one of the most commonly diagnosed cancers in the world, with an incidence of over 1 million cases and an estimated 769,000 deaths occurring in 2020. Globally, this cancer ranked fifth for cancer incidence and fourth for cancer mortality in 2020.[1,2] In 2023, there will be an estimated 26,500 new cases of gastric cancer and 11,130 deaths from gastric cancer in the United States.[3] Approximately 15% to 20% of gastric cancers are caused by pathogenic variants in hereditary gastric cancer genes.[4,5]

The genes that can predispose individuals to hereditary diffuse gastric cancer (HDGC) include the following:

• CDH1.
• CTNNA1.

HDGC is the most common hereditary cancer syndrome that can predispose individuals to gastric cancer. This disease does not have an easily detectable precursor lesion. For more information, see Hereditary Diffuse Gastric Cancer.

There are also hereditary cancer syndromes that can cause other forms of gastric cancer. These syndromes include the following:

• Lynch syndrome: Lynch syndrome is caused by pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM. The amount of gastric cancer risk associated with Lynch syndrome and the role of gastric cancer screening remain unknown, especially since a Lynch syndrome–associated gastric cancer precursor has not yet been identified.[6]
• Familial adenomatous polyposis (FAP)/gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): FAP/GAPPS are caused by pathogenic variants in APC. Gastric cancer is typically preceded by fundic gland polyps.[7]
• Peutz-Jeghers syndrome (PJS): PJS is caused by pathogenic variants in STK11. Gastric cancer is typically preceded by hamartomatous polyps.[8]
• Juvenile polyposis syndrome (JPS): JPS is caused by pathogenic variants in SMAD4 and BMPR1A. Gastric cancer is typically preceded by hamartomatous polyps.

In each of these syndromes, gastric polyps and gastric cancer risk are of secondary importance to colorectal polyps and colorectal cancer. Gastric polyp burden (including polyp count and size) and gastric cancer risk may vary between individuals.

For more information on these genetic syndromes, see Table 1.

Gastric Cancer Risk Factors

Environmental risk factors

Incidence rates for gastric cancer are the highest in Eastern Asia and Eastern Europe, while the rates in Northern America, Northern Europe, and Africa are generally low.[2] These regional differences are most likely affected by environmental and hereditary risk factors.

Environmental risk factors for gastric cancer include the following:

1. Helicobacter pylori (H. pylori) infection.

• This may be most the impactful environmental risk factor for gastric cancer.
• An H. pylori infection may cause histological changes in the stomach, which can begin with chronic, active gastritis and can progress to gastric atrophy, intestinal metaplasia, gastric dysplasia, and eventually gastric cancer.[9,10]

2. Diet.

• The regional variation in gastric cancer incidence is influenced by diet.[11,12]
• Gastric cancer risk may increase when individuals consume foods that are preserved with salt.[12,13]
• Low fruit intake and the consumption of a large amount of processed, grilled, or barbequed meats/fish may also increase gastric cancer risk.[12]

3. Migrant effects.

• Gastric cancer risk may also be affected by migrant effects (i.e., effects incurred when individuals migrate from a region with high gastric cancer risk to a region with low gastric cancer risk or vice versa).
• Studies have demonstrated that the incidence of gastric cancer in immigrants correlates closely with the incidence of gastric cancer in their new host country after one or two generations.[14,15,16]

4. Tobacco use.[12,13]

5. Alcohol use.[12,13]

6. Emerging evidence for obesity and gastroesophageal reflux disease (GERD).

• Emerging evidence suggests that there is an association between increased gastric cancer risk, excess body weight, and tissue damage associated with GERD.[17,18]

7. Racial and ethnic disparities.

• There are striking racial and ethnic disparities associated with gastric cancer incidence in the United States.[19,20,21,22,23,24]
• Studies that examine genetic and nongenetic risk factors, such as social determinants of health, are needed to understand and reduce the disparities in gastric cancer incidence that are seen in different racial and ethnic minority groups.

Data do not currently show whether these risk factors increase or decrease gastric cancer risk in individuals with hereditary gastric cancer pathogenic variants. Nevertheless, more intensive surveillance may be clinically warranted in individuals with hereditary, environmental, or ethnicity-based gastric cancer risk factors. For more information about risk factors for gastric cancer in the general population, see Stomach (Gastric) Cancer Screening.

Familial risk factors

Individuals with family histories of gastric cancer have an increased risk of developing gastric cancer.[25] For example, when individuals had a first-degree relative with gastric cancer, their relative risks to develop gastric cancer ranged from 1.5-fold to 3.5-fold in seven different studies.[26,27,28,29,30,31,32] However, these were retrospective studies, and risk estimates may have been confounded by recall bias (i.e., recalling cancers in relatives), shared environmental factors, shared dietary factors, and differing countries that studies were conducted in. The most notable of these environmental/dietary risk factors was H. pylori infection. When an individual has an H. pylori infection, other people in this individual's family also have an increased chance of developing an H. pylori infection. Smaller cohort studies have suggested the presence of a residual heritable risk for gastric cancer after correcting for the presence of H. pylori. Most of these studies did not account for hereditary gastric cancer pathogenic variants.[33] A large Scandinavian study demonstrated that the concordance value for gastric cancer was higher in monozygotic twins than it was in dizygotic twins. This suggests that gastric cancer risk may be heritable.[34]

Families with multiple gastric cancer cases have also been used to study the heritability of gastric cancer. A report by Jones in 1964 described a very large, native Maori family from New Zealand.[35] Then, in the late 1990s, Guilford et al. established genetic linkage between a cell-adhesion molecule, called CDH1, and gastric cancer cases in the original family identified in 1964 and two additional Maori families. In this study, Guilford et al. found that CDH1 was downregulated in Maori individuals with advanced gastric cancer.[35,36,37,38]Germline CDH1 pathogenic variants were first found in affected individuals in these Maori families, and later, they were also found in families around the world with hereditary diffuse gastric cancer. Subsequently, female lobular breast cancer and orofacial clefts were added to the phenotypic spectrum of CDH1 pathogenic variants.[39,40]

Precancerous Lesions

In the stomach, gastric adenocarcinoma can arise from visible lesions, from the histological progression of mucosal atrophy, or less commonly, from invisible lesions (i.e. submucosal infiltration, as seen in diffuse-type gastric adenocarcinoma). This section reviews both gastric polyps and the histological changes associated with chronic gastritis that can predispose an individual to gastric cancer.

Gastric polyps

Gastric polyps are common in the U.S. population and are found in up to 6% of individuals who undergo endoscopy. However, these polyps rarely progress to become gastric cancer.[41] When gastric polyps are isolated, they usually are sporadic in nature. However, gastric polyps can also be associated with hereditary cancer syndromes, particularly the hamartomatous and polyposis syndromes. Gastric polyps can present with the following pathologies:

• Adenomatous.
• Hyperplastic.
• Inflammatory.
• Hamartomatous (associated with PJS, JPS, and PTEN hamartoma tumor syndromes [PHTS]).
• Fundic gland.[42]

In general, the malignant potential of a polyp is determined by the polyp's histology, size, and degree of dysplasia, if present. Adenomatous and hyperplastic polyps have the highest malignant potentials, especially when H. pylori is present. In contrast, fundic gland polyps (with or without dysplasia) rarely progress to become gastric cancer, even in individuals who have FAP.[43]

Fundic gland polyps of the stomach are common and typically are associated with long-term proton pump inhibitor (PPI) use.[44] Fundic glands polyps generally do not increase gastric cancer risk because these polyps are not neoplastic in nature. However, GAPPS is an exception to this rule. In GAPPS, gastric cancer risk is strongly correlated with fundic gland polyposis. For more information about GAPPS and FAP, see Genetics of Colorectal Cancer.

Inflammatory and hyperplastic polyps can present with many different pathological features. Unlike the colon, in which hyperplastic polyps carry little or no cancer risk, hyperplastic polyps of the stomach can enlarge and develop dysplastic foci.[45] These types of polyps are not clearly associated with known hereditary gastric cancer syndromes.

Hamartomatous polyps are seen in the stomachs of patients with PJS, JPS, and PHTS. For more information on these hereditary cancer syndromes, see Genetics of Colorectal Cancer. Hamartomatous polyps are typically not dysplastic in nature. However, they can develop dysplastic foci. Consequently, these polyps can be associated with an increased gastric cancer risk, especially in individuals with hereditary gastric cancer syndromes. It is unclear if hamartomatous gastric polyps eventually become gastric cancer or if they are merely indicative of a high-risk environment in the stomach. The risk of gastric cancer is estimated by the hereditary cancer syndrome.

Gastric adenomas make up approximately 10% of all gastric polyps. A gastric adenoma's malignant potential is determined by its histological subtype and size.[46] For example, pyloric gland adenomas and intestinal-type gastric adenomas have the highest malignant potentials, while foveolar-type gastric adenomas have the lowest malignant potential.[47,48]

Chronic gastritis

Chronic gastritis, a histological diagnosis defined by the presence of a mononuclear cellular infiltrate in the lamina propria of the stomach, occurs due to environmental exposures or autoimmune gastritis. Chronic gastritis can lead to gastric intestinal metaplasia. H. pylori is the most common risk factor for intestinal metaplasia. Other risk factors for intestinal metaplasia include pernicious anemia, autoimmune gastritis, ethnicity, a family history of gastric cancer, dietary habits, smoking, and alcohol use.[49] After the development of chronic gastritis, the gastric mucosa may undergo a series of progressive changes, known as Correa's cascade, which can eventually result in gastric cancer.

The steps of Correa's cascade include the following:

1. Chronic gastritis (most commonly caused by H. pylori).
2. Gastric mucosal atrophy.
3. Gastric intestinal metaplasia.
4. Gastric dysplasia (low-grade dysplasia followed by high-grade dysplasia).[50,51]

Although these histological changes are associated with increased gastric cancer risk in the general population, the prevalence of findings and associated cancer risk in hereditary cancer syndromes is unknown. Each step in Correa's cascade only occurs in a minority of patients. There is considerable controversy regarding appropriate surveillance in patients with intestinal metaplasia.[52]

Endoscopic assessment

Gastric cancer screening is not routinely performed in the United States since gastric cancer incidence is relatively low in this population. Gastric cancer screening is also not usually performed in individuals with family histories of gastric cancer in which a hereditary gastric cancer pathogenic variant has not been identified. Large, prospective multicenter studies are needed to determine if gastric cancer screening programs would improve mortality in individuals from the United States with family histories of gastric cancer. In the United States, gastric cancer surveillance guidelines only exist for individuals with pathogenic variants in CDH1 or other gastric cancer risk genes (for more information, see Table 1).[53,54] The International Gastric Cancer Linkage Consortium recommends that individuals with family histories of diffuse gastric cancer without identifiable genetic causes (this is known as HDGC-like syndrome) participate in gastric cancer surveillance.[55] For more information, see the Definition and Management of Hereditary Diffuse Gastric Cancer (HDGC)–Like Families section in Hereditary Diffuse Gastric Cancer.

When evaluating any patient with hereditary gastric cancer risk, endoscopy includes assessment for gastric polyps and H. pylori —despite a lack of evidence demonstrating that H.pylori increases gastric cancer risk in the setting of a hereditary cancer syndrome.

A small focus of intestinal metaplasia in the antrum is shown below. Intestinal metaplasia is not always visible on endoscopy. Instead, it is often found when taking random biopsies of the stomach.[49] Emerging research has identified measures to improve endoscopic detection of such foci. Populations with high gastric intestinal metaplasia and gastric dysplasia prevalence rates have high incidence rates of gastric cancer.[49]
Endoscopic image showing a small area of intestinal metaplasia (circled in yellow) in the antrum of the stomach.

References:

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19. Shah SC, McKinley M, Gupta S, et al.: Population-Based Analysis of Differences in Gastric Cancer Incidence Among Races and Ethnicities in Individuals Age 50 Years and Older. Gastroenterology 159 (5): 1705-1714.e2, 2020.
20. Anderson WF, Rabkin CS, Turner N, et al.: The Changing Face of Noncardia Gastric Cancer Incidence Among US Non-Hispanic Whites. J Natl Cancer Inst 110 (6): 608-615, 2018.
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22. Holowatyj AN, Ulrich CM, Lewis MA: Racial/Ethnic Patterns of Young-Onset Noncardia Gastric Cancer. Cancer Prev Res (Phila) 12 (11): 771-780, 2019.
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24. Gupta S, Tao L, Murphy JD, et al.: Race/Ethnicity-, Socioeconomic Status-, and Anatomic Subsite-Specific Risks for Gastric Cancer. Gastroenterology 156 (1): 59-62.e4, 2019.
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32. Chen MJ, Wu DC, Ko YC, et al.: Personal history and family history as a predictor of gastric cardiac adenocarcinoma risk: a case-control study in Taiwan. Am J Gastroenterol 99 (7): 1250-7, 2004.
33. Yatsuya H, Toyoshima H, Tamakoshi A, et al.: Individual and joint impact of family history and Helicobacter pylori infection on the risk of stomach cancer: a nested case-control study. Br J Cancer 91 (5): 929-34, 2004.
34. Lichtenstein P, Holm NV, Verkasalo PK, et al.: Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343 (2): 78-85, 2000.
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39. Brooks-Wilson AR, Kaurah P, Suriano G, et al.: Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet 41 (7): 508-17, 2004.
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42. Gullo I, Grillo F, Mastracci L, et al.: Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes. Pathologica 112 (3): 166-185, 2020.
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44. Martin FC, Chenevix-Trench G, Yeomans ND: Systematic review with meta-analysis: fundic gland polyps and proton pump inhibitors. Aliment Pharmacol Ther 44 (9): 915-925, 2016.
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48. Chen ZM, Scudiere JR, Abraham SC, et al.: Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma. Am J Surg Pathol 33 (2): 186-93, 2009.
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Genetic Evaluation in Individuals With Personal and / or Family Histories of Gastric Cancer

Approximately 15% to 20% of gastric cancers may be caused by hereditary gastric cancer syndromes.[1,2,3] When providers suspect that an individual has a hereditary gastric cancer syndrome, it is recommended that they obtain a detailed, three-generation family history and perform genetic testing, if appropriate. The collection of a detailed personal and family history is integral for gastric cancer risk assessment.

The following items are important to elicit when collecting a patient's family history:

• Number of relatives with cancers on the same side of the family.
• Types of cancers seen in family members (including each cancer's histological subtype).^a
• Ages of family members when they were diagnosed with cancer.
• Family members' gastrointestinal polyp histories (including each polyp's histological subtype).
• Number of family members with cleft lip or cleft palate (cleft lip or cleft palate has been linked to CDH1-associated hereditary gastric cancer).[4]

^a It is recommended that family history analysis focus on gastric cancer and other cancers (such as lobular breast cancer) that may be associated with hereditary diffuse gastric cancer (HDGC).

For information on collecting a family history, see the Documenting the family history section in Cancer Genetics Risk Assessment and Counseling.

In busy clinical settings, it might not be feasible to obtain a complete family history.[5] Studies have found that people often have incomplete or inaccurate information about the cancers that occurred in their relatives.[6,7,8,9] Furthermore, patients often over- or under-report the number of individuals in their families who have had gastric cancer.

Many factors can contribute to inaccurate reporting of a gastric cancer family history. In medicine, the stomach has a distinct definition and anatomical location in the body. The public's definition of the stomach is more ambiguous, and this could lead to reporting inaccuracies.[7] There are multiple organs inside the abdominal cavity that patients could confuse with the stomach. Studies have demonstrated that many patients do not know where organs are located in the body.[10]

The poor validity of self-reported gastric cancer family histories needs to be considered during a patient's genetic evaluation and when creating an individual's clinical management recommendations. Studies have assessed the accuracy of self-reported family histories by comparing collected information with confirmation sources like death certificates, cancer registries, and histopathological records.[6,7,8,9,11] One retrospective study from the United Kingdom compared 595 clinical notes to confirmation sources. This study found increased error when patients reported malignancies located in the abdominal cavity.[7] A systematic review found that only 22% to 67% of reported stomach cancer diagnoses were verified by confirmation sources.[11] For more information, see the Accuracy of the family history section in Cancer Genetics Risk Assessment and Counseling.

Obtaining pathological documentation of personal/family histories of cancer and polyps is also integral when assessing a patient's hereditary gastric cancer risk. This is especially important because genetic testing criteria has shifted over the years and has, in turn, broadened clinical criteria.[12] It is important to obtain pathology reports from patients to confirm the histological subtypes of cancers when possible. Signet ring cell carcinoma, diffuse gastric cancer, and poorly differentiated carcinoma pathologies are characteristic of hereditary gastric cancer syndromes, particularly CDH1-associated HDGC. These histologies are commonly associated with linitis plastica (i.e., diffusely infiltrated, non-distensible stomach). Multiple gastrointestinal polyps (e.g., tubular adenomas, hamartomas) are associated with other hereditary cancer syndromes, such as Peutz-Jeghers syndrome, juvenile polyposis syndrome, familial adenomatous polyposis (FAP) /gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).[13] Fundic gland polyps are one of the most common findings on routine upper endoscopies. While these fundic gland polyps are a characteristic finding in individuals with FAP, they are also found often in individuals in the general population who take proton pump inhibitors. Hence, fundic gland polyps are not usually indicative of an underlying hereditary cancer syndrome. For more information about the cellular classification of gastric cancers, see Gastric Cancer Treatment.

The diagnosis of cancers before age 50 years is a hallmark feature of hereditary cancer syndromes. Attenuated forms of hereditary cancer syndromes also exist and are increasingly recognized. In these attenuated syndromes, the ages of gastric cancer onset can occur after age 50 years.[14]

Genetic Testing Approach

Patients who develop gastric cancer usually present at an advanced stage.[15] This is important to consider when selecting a genetic testing approach. Genetic testing is time-sensitive for patients with advanced gastric cancer and should include informed consent, sample collection, and an explanation of genetic test results.[16] However, the timing of genetic testing will need to be balanced with the patient's competing treatment priorities and performance status. For more information, see the Value of testing an affected family member first section in Cancer Genetics Risk Assessment and Counseling.

Germline genetic testing criteria exists for the following genes associated with gastric cancer and/or gastric polyps: CDH1, CTNNA1, APC, STK11, SMAD4, and the Lynch syndrome genes (MLH1, MSH2, MSH6, EPCAM).[12] One possible genetic testing approach is to first test for gene(s) in which clinical criteria for hereditary cancer syndrome(s) are met. This approach may not be ideal when a patient's family history includes cancers that can be associated with multiple hereditary gastric cancer syndromes. This can create a lengthy and expensive evaluation process if each suspected gene is tested sequentially after uninformative results. When the cancers in a family history overlap with multiple hereditary gastric cancer syndromes, providers can first test the gene(s) at the top of the differential diagnosis list. If pathogenic variants are not identified, providers can then reflex to a larger hereditary gastric cancer multigene panel. If this single gene genetic testing approach is preferred, providers may need to identify a lab that offers the option to reflex to other genes before beginning the genetic testing process.

When the patient has multiple cancers in the family that overlap with more than one hereditary cancer syndrome, another option is ordering multigene panel testing for all suspected genes. Multigene panel testing is the simultaneous testing of many genes for pathogenic and likely pathogenic variants, often at costs comparable to single-gene genetic testing. Hereditary cancer multigene panel testing includes cancer site-specific panels, high- or moderate-risk gene panels, guideline-based panels, and pancancer panels.[17] Given the numerous panel testing options, clinicians must pay special attention to choose the most appropriate panel of genes based on each individual patient's differential diagnosis. For instance, genetic testing for pathogenic variants in both CDH1 and CTNNA1 is recommended when testing criteria for HDGC is met. Additionally, analysis of promoter 1B in the APC gene must be included when testing for GAPPS.

For more information about selecting the appropriate genetic test, see the Determining the Test to be Used section in Cancer Genetics Risk Assessment and Counseling.

Multigene panel testing implications

This section briefly summarizes the implications for patients undergoing multigene panel testing for hereditary gastric cancer syndromes. For more information about multigene panel testing, including genetic education, counseling considerations, and research, see the Multigene (panel) testing section in Cancer Genetics Risk Assessment and Counseling.

Multigene panel testing can present challenges, including the unexpected discovery of pathogenic variants in genes that would not have been considered based on the patient's personal and/or family history. Pathogenic variants in many hereditary cancer genes can increase an individual's risk of developing more than one type of cancer. For instance, CDH1 pathogenic variants are associated with increased risk for both diffuse gastric cancer and lobular breast cancer.[14,18,19] Gastric cancer risk management dilemmas arise when individuals with only a personal and/or family history of breast cancer find an unexpected CDH1 pathogenic variant on multigene panel testing. This test result can complicate medical decision-making, since these individuals would not normally participate in enhanced gastric cancer screening based on their personal or family histories alone. Furthermore, there are no effective gastric cancer screening recommendations for CDH1 carriers. Therefore, all individuals with a pathogenic variant in CDH1 are counseled about the option of risk-reducing total gastrectomy, a surgery with postoperative complication rates as high as 10% and a high likelihood of chronic sequelae.[12,20] The discovery of an unexpected CDH1 variant on multigene panel testing in the absence of a family history of gastric cancer is a challenging situation that is being increasingly encountered in clinical practice.[21,22] Pretest genetic counseling is recommended when patients undergo multigene panel testing. Pretest genetic counseling may include a discussion about potential unexpected genetic test findings, and the implications of identifying pathogenic variants in genes that are not well understood, including a review of any limitations associated with cancer risk management recommendations.[22,23]

Cascade genetic testing

Cascade genetic testing identifies relatives who are at risk for a genetic condition by following the logical path of a pathogenic variant in a family. Cascade genetic testing is routinely offered to at-risk relatives once a pathogenic variant is identified. For more information, see the Cascade Genetic Testing of Family Members section in Cancer Genetics Risk Assessment and Counseling. In some cases, the patient will already have advanced gastric cancer when a CDH1 pathogenic variant is found. Many patients do not have symptoms of gastric cancer until it has advanced to later stages. Gastric cancer is often incurable, and only 31% of patients diagnosed with gastric cancer survive 5 years or more.[15] Patients may be declining when they receive their genetic test results and may be unable to communicate this result to family members. Ideally, probands and clinicians would work together to identify at-risk relatives for cascade testing.[24] Since gastric cancer screening is not performed in the general population, cascade genetic testing is critical to identify asymptomatic high-risk individuals who may benefit from personalized gastric cancer management recommendations.

References:

1. Uson PLS, Kunze KL, Golafshar MA, et al.: Germline Cancer Testing in Unselected Patients with Gastric and Esophageal Cancers: A Multi-center Prospective Study. Dig Dis Sci 67 (11): 5107-5115, 2022.
2. Ku GY, Kemel Y, Maron SB, et al.: Prevalence of Germline Alterations on Targeted Tumor-Normal Sequencing of Esophagogastric Cancer. JAMA Netw Open 4 (7): e2114753, 2021.
3. Oliveira C, Pinheiro H, Figueiredo J, et al.: Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol 16 (2): e60-70, 2015.
4. Frebourg T, Oliveira C, Hochain P, et al.: Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet 43 (2): 138-42, 2006.
5. Qureshi N, Wilson B, Santaguida P, et al.: Collection and use of cancer family history in primary care. Evid Rep Technol Assess (Full Rep) (159): 1-84, 2007.
6. Mitchell RJ, Brewster D, Campbell H, et al.: Accuracy of reporting of family history of colorectal cancer. Gut 53 (2): 291-5, 2004.
7. Douglas FS, O'Dair LC, Robinson M, et al.: The accuracy of diagnoses as reported in families with cancer: a retrospective study. J Med Genet 36 (4): 309-12, 1999.
8. Ozanne EM, O'Connell A, Bouzan C, et al.: Bias in the reporting of family history: implications for clinical care. J Genet Couns 21 (4): 547-56, 2012.
9. Mai PL, Garceau AO, Graubard BI, et al.: Confirmation of family cancer history reported in a population-based survey. J Natl Cancer Inst 103 (10): 788-97, 2011.
10. Rashid A, Jagger C: Patients' knowledge of anatomical location of major organs within the human body: a comparison between Asians and non-Asians. Fam Pract 13 (5): 450-4, 1996.
11. Fiederling J, Shams AZ, Haug U: Validity of self-reported family history of cancer: A systematic literature review on selected cancers. Int J Cancer 139 (7): 1449-60, 2016.
12. Blair VR, McLeod M, Carneiro F, et al.: Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol 21 (8): e386-e397, 2020.
13. Colvin H, Yamamoto K, Wada N, et al.: Hereditary Gastric Cancer Syndromes. Surg Oncol Clin N Am 24 (4): 765-77, 2015.
14. Xicola RM, Li S, Rodriguez N, et al.: Clinical features and cancer risk in families with pathogenic CDH1 variants irrespective of clinical criteria. J Med Genet 56 (12): 838-843, 2019.
15. National Cancer Institute: SEER Stat Fact Sheets: Stomach Cancer. Bethesda, Md: National Cancer Institute. Available online. Last accessed March 19, 2024.
16. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015.
17. Domchek SM, Bradbury A, Garber JE, et al.: Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol 31 (10): 1267-70, 2013.
18. Pharoah PD, Guilford P, Caldas C, et al.: Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121 (6): 1348-53, 2001.
19. Corso G, Intra M, Trentin C, et al.: CDH1 germline mutations and hereditary lobular breast cancer. Fam Cancer 15 (2): 215-9, 2016.
20. van der Kaaij RT, van Kessel JP, van Dieren JM, et al.: Outcomes after prophylactic gastrectomy for hereditary diffuse gastric cancer. Br J Surg 105 (2): e176-e182, 2018.
21. Lowstuter K, Espenschied CR, Sturgeon D, et al.: Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges. JCO Precis Oncol 1: 1-12, 2017.
22. Katona BW, Clark DF, Domchek SM: CDH1 on Multigene Panel Testing: Look Before You Leap. J Natl Cancer Inst 112 (4): 330-334, 2020.
23. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 3.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed May 31, 2023.
24. Hampel H: Genetic counseling and cascade genetic testing in Lynch syndrome. Fam Cancer 15 (3): 423-7, 2016.

Major Genes and Genetic Syndromes Associated With Gastric Cancer

The major heritable syndromes associated with increased gastric cancer risk are listed in Table 1, along with their corresponding susceptibility genes. For more information on CDH1- and CTNNA1-associated hereditary gastric cancers, see Hereditary Diffuse Gastric Cancer. The gastric cancer risk of the other syndromes in this table are described throughout this summary and hyperlinks have also been provided to other PDQ summaries with additional information.

Table 1. Hereditary Syndromes Associated With Increased Gastric Cancer Risk

Syndromea	Gene	Gastric Cancer Risk	Gastric Cancer Pathology	Gastric CancerSurveillance	Other Characteristics
CNS = central nervous system; CRC = colorectal cancer; EGD = esophagogastroduodenoscopy; GI = gastrointestinal; GIST = gastrointestinal stromal tumor.
a All conditions are inherited in anautosomal dominantfashion, unless otherwise specified.
b High risk lesions include tubular adenomas, polyps with high-grade dysplasia, and pyloric gland adenomas.
c Prophylactic total gastrectomy is not recommended prior to age 40 y. However, it may be considered for certain patients, especially those with a family histories of gastric cancer prior to age 25 y.
Hereditary diffuse gastric cancer	CDH1andCTNNA1	33%–83%[1,2,3,4,5]	Diffuse type, signet ring cell carcinoma	EGD with multiple random biopsies of the stomach every 6–12 moor risk-reducing total gastrectomy between ages 18–40 yc[6]	For CDH1 only: Lobular breast cancer, cleft lip or cleft palate. It is currently unknown whetherCTNNA1is associated with lobular breast cancer or cleft lip or cleft palate
Familial adenomatous polyposis syndrome(FAP)	APC	1.3%–5% in FAP and AFAP.[7,8]	Intestinal type	EGD for duodenal surveillance is also adequate surveillance for gastric cancers. Gastrectomy can be considered for patients with high-risk lesions that cannot be managed endoscopicallyb[9]	Gastric polyps (fundic gland polyps and adenomas), CRC, colorectal polyps (adenomas), desmoid tumors, duodenal tumors and cancer, thyroid cancer, brain cancer, ampullary cancer, pancreatic cancer, hepatoblastoma
Attenuated familial adenomatous polyposis(AFAP)	APC
Gastric adenocarcinoma and proximal polyposis of the stomach(GAPPS)	APC(pathogenic variants/pointmutationsin the promoter 1B region ofAPCare associated with GAPPS-7)	In GAPPS, gastric cancer risk is significantly increased, but exact risk numbers are unknown[10]
Lynch syndrome(also known as hereditary nonpolyposis colorectal cancer [HNPCC])	MLH1,MSH2,MSH6,PMS2,EPCAM	0.2%–9%	Intestinal type	Upper GI surveillance with EGD (preferably performed in conjunction with colonoscopy) starting at age 30–40 y (or earlier based on the patient's family history). Repeat EGD every 2–4 y[9]	CRC, endometrial cancer, ovarian cancer, breast cancer, pancreatic cancer, bladder cancer, biliary tract cancer, urothelial cancer, small bowel cancer, prostate cancer, brain/CNS tumor
Peutz-Jeghers syndrome	STK11(also known asLKB1)	29%[9]	Intestinal type (arising from dysplasia in hamartomas)	EGD every 2–3 y beginning in the late adolescence[9]	Hamartomatous GI polyps; breast cancer; CRC; small bowel cancer; pancreatic cancer; Sertoli cell tumors of the ovary and testes; cervical adenoma malignum; endometrial cancer; lung cancer; mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia and/or fingers
Juvenile polyposis syndrome	SMAD4,BMPR1A	21% if multiple polyps are present	Intestinal type (arising from dysplasia in juvenile polyps/hamartomas)	EGD every 2–3 y. If polyps are found, conduct EGD at shorter intervals based on polyp size, number, and pathology[9]	Juvenile/hamartomatous colorectal polyps, CRC, hereditary hemorrhagic telangiectasia
Li-Fraumeni syndrome	TP53	2.8%	Possibly intestinal type		Breast cancer, adrenocortical carcinoma, sarcoma, brain/CNS tumor, leukemia
Carney-Stratakis syndromeand hereditary pheochromocytoma/paraganglioma (PHEO/PGL) syndrome	MAX,SDHA,SDHAF2,SDHB,SDHC,SDHD,TMEM127	Increased risk (exact risk unknown)	GIST		PHEO, PGL, pulmonary chondroma, clear cell renal cell carcinoma, papillary thyroid carcinoma, pituitary adenomas, and neuroendocrine tumors

References:

1. Roberts ME, Ranola JMO, Marshall ML, et al.: Comparison of CDH1 Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers. JAMA Oncol 5 (9): 1325-1331, 2019.
2. Pharoah PD, Guilford P, Caldas C, et al.: Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121 (6): 1348-53, 2001.
3. Hansford S, Kaurah P, Li-Chang H, et al.: Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol 1 (1): 23-32, 2015.
4. Kaurah P, MacMillan A, Boyd N, et al.: Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 297 (21): 2360-72, 2007.
5. Xicola RM, Li S, Rodriguez N, et al.: Clinical features and cancer risk in families with pathogenic CDH1 variants irrespective of clinical criteria. J Med Genet 56 (12): 838-843, 2019.
6. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer. Version 1.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed June 29, 2023.
7. Cannon AR, Keener M, Neklason D, et al.: Surgical Interventions, Malignancies, and Causes of Death in a FAP Patient Registry. J Gastrointest Surg 25 (2): 452-456, 2021.
8. Mankaney G, Leone P, Cruise M, et al.: Gastric cancer in FAP: a concerning rise in incidence. Fam Cancer 16 (3): 371-376, 2017.
9. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2023. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2023. Available with free registration. Last accessed June 28, 2023.
10. Li J, Woods SL, Healey S, et al.: Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. Am J Hum Genet 98 (5): 830-842, 2016.

Other Genes Associated with Gastric Cancer

Preliminary evidence has linked gastric cancer to other genes that are not typically associated with gastric cancer, such as ATM, BRCA1, BRCA2, BRIP1, and RAD51D. Studies suggest a possible association between gastric cancer risk and pathogenic variants in both established gastric cancer genes and in moderate- and high-risk genes that are not typically associated with gastric cancer. However, clinical practice changes are not indicated based on this preliminary evidence.

• Fifty-one adults with gastric cancer (with any type of histology) were part of an international hereditary cancer research network. These individuals were retrospectively selected to undergo germline genetic testing with a 706–candidate gene genetic testing panel.[1] Twenty pathogenic or likely pathogenic variants were identified in 18 participants (35%). Some of these pathogenic variants were in genes not typically associated with gastric cancer, including ATM, BRCA2, BRIP1, FANCC, and TP53.
• Another study of 34 patients with gastric cancer, who were not selected based on their clinical characteristics or family histories of cancer, found a pathogenic variant rate of 17.6% on a genetic testing panel that examined between 83 and 84 genes.[2] Two pathogenic variants were identified in BRCA1, and one pathogenic variant was identified in each of the following genes: BRCA2, CDH1, FH, and SDHA.
• A cross-sectional study performed at a tertiary cancer center assessed the presence of pathogenic variants on a genetic testing panel that examined 76 or 88 genes in 243 patients with gastric cancer who consented to paired somatic and germline sequencing.[3] A total of 48 patients with gastric cancer (19.8%) had germline pathogenic variants. In high- and moderate-penetrance genes that are not classically associated with gastric cancer, pathogenic variants were found most frequently in BRCA1, BRCA2, and ATM.
• One of the largest studies included 282 patients with gastric cancer who were of Han Chinese descent.[4] These patients were enrolled at medical centers in Beijing and underwent a 69–cancer gene panel, which revealed that 7.1% of patients had pathogenic variants. Pathogenic variants were found most often in ATM (detection rate, 1.1% [3/282 patients]), followed by BRCA1, BRIP1, and RAD51D, which all had a detection rate of 0.7% (2/282 patients).

Additional studies are warranted to determine if there is a causal relationship between these genes and gastric cancer risk. However, the rate of pathogenic variants found in these studies supports the use of multigene panels in patients with gastric cancer undergoing germline genetic testing. For more information, see the Other Cancer Risks section in BRCA1 and BRCA2: Cancer Risks and Management.

References:

1. Slavin T, Neuhausen SL, Rybak C, et al.: Genetic Gastric Cancer Susceptibility in the International Clinical Cancer Genomics Community Research Network. Cancer Genet 216-217: 111-119, 2017.
2. Uson PLS, Kunze KL, Golafshar MA, et al.: Germline Cancer Testing in Unselected Patients with Gastric and Esophageal Cancers: A Multi-center Prospective Study. Dig Dis Sci 67 (11): 5107-5115, 2022.
3. Ku GY, Kemel Y, Maron SB, et al.: Prevalence of Germline Alterations on Targeted Tumor-Normal Sequencing of Esophagogastric Cancer. JAMA Netw Open 4 (7): e2114753, 2021.
4. Ji K, Ao S, He L, et al.: Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma. Chin J Cancer Res 32 (4): 508-515, 2020.

Latest Updates to This Summary (10 / 27 / 2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Added Other Genes Associated with Gastric Cancer as a new section.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of gastric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Genetics of Gastric Cancer are:

• Grace-Ann O. Fasaye, ScM, CGC (National Cancer Institute)
• Gautam Mankaney, MD (Virginia Mason Franciscan Health)

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PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Gastric Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/stomach/hp/gastric-genetics-pdq. Accessed <MM/DD/YYYY>.

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Last Revised: 2023-10-27