Gastric adenocarcinoma (GAC) is the fifth most common cancer in the world, and the presence of germline pathogenic variants has been linked with approximately 5% of gastric cancer diagnoses. Multiple GAC susceptibility genes have been identified, but information regarding the risk associated with pathogenic variants in these genes remains obscure. We conducted a systematic review of existing studies reporting the penetrance of GAC susceptibility genes.
A structured search query was devised to identify GAC-related papers indexed in MEDLINE/PubMed. A semi-automated natural language processing algorithm was applied to identify penetrance papers for inclusion. Original studies reporting the penetrance of GAC were included and the full-text articles were independently reviewed. Summary statistics, effect estimates, and precision parameters from these studies were compiled into a table using a predetermined format to ensure consistency.
Forty-five studies were identified reporting the penetrance of GAC among patients harboring mutations in 13 different genes: APC, ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, MUTYH-Monoallelic, NBN, and STK11.
Our systematic review highlights the importance of testing for germline pathogenic variants in patients before the development of GAC. Management of patients who harbor a pathogenic mutation is multifactorial, and clinicians should consider cancer risk for each applicable gene–cancer association throughout the screening and management process. The scarcity of studies we found investigating the risk of GAC among patients with pathogenic variants in GAC susceptibility genes highlights the need for more investigations that focus on producing robust risk estimates for gene–cancer associations.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Availability of Data, Code, and Other Materials
The NLP code used in this review has been made publicly available online at https://github.com/YujiaBao/PubmedClassifier. Annotated data can be made available to researchers who wish to collaborate on expanding the cancer gene knowledge base. Please contact the corresponding author, Kevin S. Hughes, MD, FACS, for more information.
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.
Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21114012.
Lauwers GY, Mullen JT, Chelcun Schreiber KE, Chung DC. Familial gastric cancers: a review with focus on hereditary diffuse gastric cancer syndrome. AJSP Rev Rep. 2014;19(2):66–73. https://doi.org/10.1097/pcr.0000000000000030.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Gastric Cancer Version 2.2022 – 11 January 2022.
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. 2016;98(5):830–42. https://doi.org/10.1016/j.ajhg.2016.03.001.
Colvin H, Yamamoto K, Wada N, Mori M. Hereditary gastric cancer syndromes. Surg Oncol Clin N Am. 2015;24(4):765–77. https://doi.org/10.1016/j.soc.2015.06.002.
McKinley SK, Singh P, Yin K, et al. Disease spectrum of gastric cancer susceptibility genes. Medical Oncology. 2021;38(5):1–10.
Hansford S, Kaurah P, Li-Chang H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015;1(1):23–32. https://doi.org/10.1001/jamaoncol.2014.168.
Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni syndrome. 1999. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1311/.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal V. 1.2017. NCCN Clinical Practice Guidelines; 2017.
Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1. https://doi.org/10.1186/2046-4053-4-1.
Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647. https://doi.org/10.1136/bmj.g7647.
Bao Y, Deng Z, Wang Y, et al. Using machine learning and natural language processing to review and classify the medical literature on cancer susceptibility genes. JCO Clin Cancer Inform. 2019;3:1–9. https://doi.org/10.1200/CCI.19.00042.
Deng Z, Yin K, Bao Y, et al. Validation of a semiautomated natural language processing-based procedure for meta-analysis of cancer susceptibility gene penetrance. JCO Clin Cancer Inform. 2019;3:1–9. https://doi.org/10.1200/CCI.19.00043.
Park JG, Park KJ, Ahn YO, et al. Risk of gastric cancer among Korean familial adenomatous polyposis patients. Report of three cases. Dis Colon Rectum. 1992;35(10):996–8. https://doi.org/10.1007/BF02253505.
Hall MJ, Bernhisel R, Hughes E, et al. Germline pathogenic variants in the ataxia telangiectasia mutated (ATM) gene are associated with high and moderate risks for multiple cancers. Cancer Prev Res (Phila). 2021;14(4):433–40. https://doi.org/10.1158/1940-6207.CAPR-20-0448.
Helgason H, Rafnar T, Olafsdottir HS, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet. 2015;47(8):906–10. https://doi.org/10.1038/ng.3342.
Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005;97(11):813–22. https://doi.org/10.1093/jnci/dji141.
Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700–10. https://doi.org/10.1086/318787.
Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002;94(18):1365–72. https://doi.org/10.1093/jnci/94.18.1365.
Ławniczak M, Jakubowska A, Białek A, et al. BRCA1 founder mutations do not contribute to increased risk of gastric cancer in the Polish population. Hered Cancer Clin Pract. 2016;14:3. https://doi.org/10.1186/s13053-015-0043-0.
Kim H, Choi DH, Park W, et al. The association between non-breast and ovary cancers and BRCA mutation in first- and second-degree relatives of high-risk breast cancer patients: a large-scale study of Koreans. Hered Cancer Clin Pract. 2019;17:1. https://doi.org/10.1186/s13053-018-0103-3.
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. 2019;5(9):1325–31. https://doi.org/10.1001/jamaoncol.2019.1208.
Pharoah PD, Guilford P, Caldas C. Consortium IGCL. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121(6):1348–53. https://doi.org/10.1053/gast.2001.29611.
Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297(21):2360–72. https://doi.org/10.1001/jama.297.21.2360.
Xicola RM, Li S, Rodriguez N, et al. Clinical features and cancer risk in families with pathogenic. J Med Genet. 2019;56(12):838–43. https://doi.org/10.1136/jmedgenet-2019-105991.
Teodorczyk U, Cybulski C, Wokołorczyk D, et al. The risk of gastric cancer in carriers of CHEK2 mutations. Fam Cancer. 2013;12(3):473–8. https://doi.org/10.1007/s10689-012-9599-2.
Cybulski C, Górski B, Huzarski T, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75(6):1131–5. https://doi.org/10.1086/426403.
Näslund-Koch C, Nordestgaard BG, Bojesen SE. Increased risk for other cancers in addition to breast cancer for CHEK2*1100delC heterozygotes estimated from the copenhagen general population study. J Clin Oncol. 2016;34(11):1208–16. https://doi.org/10.1200/JCO.2015.63.3594.
Win AK, Reece JC, Dowty JG, et al. Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH. Int J Cancer. 2016;139(7):1557–63. https://doi.org/10.1002/ijc.30197.
Win AK, Cleary SP, Dowty JG, et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer. 2011;129(9):2256–62. https://doi.org/10.1002/ijc.25870.
Ebi H, Matsuo K, Sugito N, et al. Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of cancer. Cancer Res. 2007;67(23):11158–65. https://doi.org/10.1158/0008-5472.CAN-07-1749.
Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000;119(6):1447–53. https://doi.org/10.1053/gast.2000.20228.
Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med. 1987;316(24):1511–4. https://doi.org/10.1056/NEJM198706113162404.
Spigelman AD, Murday V, Phillips RK. Cancer and the Peutz-Jeghers syndrome. Gut. 1989;30(11):1588–90. https://doi.org/10.1136/gut.30.11.1588.
Westerman A, Entius M, van Velthuysen M, et al. Cancer risk in Peutz-Jeghers syndrome. European Journal of Gastroenterology & Hepatology. 1998;10(12):A42.
Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. 1998;128(11):896–9. https://doi.org/10.7326/0003-4819-128-11-199806010-00004.
Foley TR, McGarrity TJ, Abt AB. Peutz-Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up. Gastroenterology. 1988;95(6):1535–40. https://doi.org/10.1016/s0016-5085(88)80074-x.
Burdick D, Prior JT. Peutz-Jeghers syndrome. A clinicopathologic study of a large family with a 27-year follow-up. Cancer. 1982;50(10):2139-2146. doi: https://doi.org/10.1002/1097-0142(19821115)50:10<2139::aid-cncr2820501028>3.0.co;2-k
Dowty JG, Win AK, Buchanan DD, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat. 2013;34(3):490–7. https://doi.org/10.1002/humu.22262.
Saita C, Yamaguchi T, Horiguchi SI, et al. Tumor development in Japanese patients with Lynch syndrome. PLoS One. 2018;13(4):e0195572. https://doi.org/10.1371/journal.pone.0195572.
Engel C, Loeffler M, Steinke V, et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol. 2012;30(35):4409–15. https://doi.org/10.1200/JCO.2012.43.2278.
Capelle LG, Van Grieken NC, Lingsma HF, et al. Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in The Netherlands. Gastroenterology. 2010;138(2):487–92. https://doi.org/10.1053/j.gastro.2009.10.051.
Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet. 2009;75(2):141–9. https://doi.org/10.1111/j.1399-0004.2008.01125.x.
Møller P, Seppälä TT, Bernstein I, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2018;67(7):1306–16. https://doi.org/10.1136/gutjnl-2017-314057.
Watson P, Vasen HFA, Mecklin JP, et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008;123(2):444–9. https://doi.org/10.1002/ijc.23508.
Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22):2304–10. https://doi.org/10.1001/jama.2011.743.
Vasen HF, Stormorken A, Menko FH, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19(20):4074–80. https://doi.org/10.1200/JCO.2001.19.20.4074.
Win AK, Lindor NM, Young JP, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012;104(18):1363–72. https://doi.org/10.1093/jnci/djs351.
Geary J, Sasieni P, Houlston R, et al. Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Fam Cancer. 2008;7(2):163–72. https://doi.org/10.1007/s10689-007-9164-6.
Stuckless S, Parfrey PS, Woods MO, et al. The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome. Fam Cancer. 2007;6(1):1–12. https://doi.org/10.1007/s10689-006-0014-8.
Fan Y, Liu X, Zhang H, et al. Variations in exon 7 of the MSH2 gene and susceptibility to gastrointestinal cancer in a Chinese population. Cancer Genet Cytogenet. 2006;170(2):121–8. https://doi.org/10.1016/j.cancergencyto.2006.05.010.
Aarnio M, Mecklin JP, Aaltonen LA, Nyström-Lahti M, Järvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 1995;64(6):430–3. https://doi.org/10.1002/ijc.2910640613.
Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81(2):214–8. https://doi.org/10.1002/(sici)1097-0215(19990412)81:2%3c214::aid-ijc8%3e3.0.co;2-l.
Marques-de-Sá I, Castro R, Pita I, Dinis-Ribeiro M, Brandão C. Cancer-risk by family history and mismatch-repair mutation in Lynch syndrome. Scand J Gastroenterol. 2020;55(6):701–5. https://doi.org/10.1080/00365521.2020.1766553.
Cho H, Yamada M, Sekine S, et al. Gastric cancer is highly prevalent in Lynch syndrome patients with atrophic gastritis. Gastric Cancer. 2021;24(2):283–91. https://doi.org/10.1007/s10120-020-01113-0.
Ikenoue T, Arai M, Ishioka C, et al. Importance of gastric cancer for the diagnosis and surveillance of Japanese Lynch syndrome patients. J Hum Genet. 2019;64(12):1187–94. https://doi.org/10.1038/s10038-019-0674-5.
Yamaguchi T, Furukawa Y, Nakamura Y, et al. Comparison of clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients with colorectal cancer: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum. Jpn J Clin Oncol. 2015;45(2):153–9. https://doi.org/10.1093/jjco/hyu190.
Park YJ, Shin KH, Park JG. Risk of gastric cancer in hereditary nonpolyposis colorectal cancer in Korea. Clin Cancer Res. 2000;6(8):2994–8.
Bermejo JL, Eng C, Hemminki K. Cancer characteristics in Swedish families fulfilling criteria for hereditary nonpolyposis colorectal cancer. Gastroenterology. 2005;129(6):1889–99. https://doi.org/10.1053/j.gastro.2005.09.012.
Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30(9):958–64. https://doi.org/10.1200/JCO.2011.39.5590.
Pande M, Wei C, Chen J, et al. Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry. Fam Cancer. 2012;11(3):441–7. https://doi.org/10.1007/s10689-012-9534-6.
Ericson K, Nilbert M, Bladström A, Anderson H, Olsson H, Planck M. Familial risk of tumors associated with hereditary non-polyposis colorectal cancer: a Swedish population-based study. Scand J Gastroenterol. 2004;39(12):1259–65. https://doi.org/10.1080/00365520410003506.
Therkildsen C, Ladelund S, Smith-Hansen L, Lindberg LJ, Nilbert M. Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra-colorectal cancer types. Br J Cancer. 2017;117(11):1702–10. https://doi.org/10.1038/bjc.2017.348.
National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal Version 2.2021–26 April 2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Published 2022. Accessed 23 May 2022.
Gayther SA, Gorringe KL, Ramus SJ, et al. Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res. 1998;58(18):4086–9.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 2.2022–9 March 2022.
Chamseddine RS, Wang C, Yin K, et al. Penetrance of male breast cancer susceptibility genes: a systematic review. Breast Cancer Res Treat. 2022;191(1):31–8. https://doi.org/10.1007/s10549-021-06413-2.
The authors wish to acknowledge their colleague, Dr. Mark Robson, who provided expertise that greatly assisted the research and construction of this manuscript.
Kevin Hughes receives honoraria from Hologic (surgical implant for radiation planning with breast conservation and wire-free breast biopsy), TME (Targeted Medical Education, genetics education and consulting), MedNeon (genetics education company), and Myriad Genetics. He also has a financial interest in CRA Health (formerly Hughes RiskApps), which was recently acquired by Volpara; CRA Health develops risk assessment models/software with a particular focus on breast cancer and colorectal cancer, and Kevin Hughes is a founder of the company. He is also the Co-Creator of Ask2Me.Org, which is freely available for clinical use and is licensed for commercial use by the Dana Farber Cancer Institute and the Massachusetts General Hospital (MGH). His interests in CRA Health and Ask2Me.Org were reviewed and are managed by MGH and Partners Health Care in accordance with their conflict of interest policies. Sahar Hosseini, Ahmet Acar, Meghdeep Sen, Kiersten Meeder, Preeti Singh, Kanhua Yin, and Jeffrey M. Sutton declare that they have no conflicts of interest.
This systematic review is not registered with the International Prospective Register of Systematic Reviews (PROSPERO).
A protocol was not prepared for this review.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Hosseini, S., Acar, A., Sen, M. et al. Penetrance of Gastric Adenocarcinoma Susceptibility Genes: A Systematic Review. Ann Surg Oncol 30, 1795–1807 (2023). https://doi.org/10.1245/s10434-022-12829-x