Hereditary diffuse gastric cancer
- Pamela Hebbard, MD, FRCS
Pamela Hebbard, MD, FRCS
- Assistant Professor of Surgery
- University of Manitoba and CancerCare Manitoba
- Kasmintan A Schrader, MBBS, FRCPC, PhD
Kasmintan A Schrader, MBBS, FRCPC, PhD
- Medical Genetics
- University of British Columbia
- David Huntsman, MD, FRCPC, FCCMG
David Huntsman, MD, FRCPC, FCCMG
- Professor of Pathology and Laboratory Medicine
- University of British Columbia
Hereditary diffuse gastric cancer (HDGC) is an inherited form of diffuse type gastric cancer, a highly invasive tumor that is characterized by late presentation and a poor prognosis. Many families with HDGC have germline mutations in the E-cadherin (CDH1) gene that are inherited in an autosomal dominant pattern. The lifetime risk of gastric cancer in individuals from these families is very high, and the median age at diagnosis is only 38. As a result, prophylactic total gastrectomy is usually advised, generally between ages 20 and 30.
This topic will provide a detailed overview of HDGC, focusing on the identification of high-risk families and genetic counseling and testing. The molecular pathogenesis of this disorder and technical aspects of prophylactic total gastrectomy for patients with HDGC are presented separately. (See "Pathology and molecular pathogenesis of gastric cancer", section on 'Diffuse type cancers' and "Surgical management of hereditary diffuse gastric cancer".)
HDGC is inherited as an autosomal dominant trait with high penetrance. Germline truncating mutations of the CDH1 gene, located on chromosome 16q22.1, were originally described in three Maori families from New Zealand that were predisposed to diffuse gastric cancer. Subsequently, germline CDH1 mutations have been identified in approximately 15 to 50 percent of affected kindreds that meet the clinical criteria for HDGC, as defined by the International Gastric Cancer Linkage Consortium (IGCLC) . (See 'Identification of high-risk families' below.)
The wide range of this estimate has to do with both the background incidence of gastric cancer and the criteria used to define the syndrome:
●For the most part, the frequency of mutation detection varies inversely with the background incidence of gastric cancer. Thus CDH1 mutation detection rates in families meeting HDGC criteria are highest (40 to 52.6 percent) in lower-incidence countries like Canada, the United States, and the United Kingdom  and lower in moderate-incidence countries like Germany (25 percent), and lowest in high-incidence countries like Portugal and Italy (22.2 percent)  and Japan (15.4 percent) . A more recent series of 183 index cases meeting the 2010 IGCLC clinical criteria for CDH1 testing  from Canada, Portugal, and Italy reported a lower than expected detection rate for a pathogenic CDH1 mutation (19 percent) . However, across 144 CDH1 mutation-negative HDGC probands, other potential candidate mutations were identified in 16 (11 percent), including mutations in CTNNA1 (the gene for alpha-catenin), BRCA2 (the gene associated with Hereditary Breast and Ovarian Cancer syndrome), STK11 (the gene associated with Peutz-Jeghers syndrome), SDHB, PRSS1, ATM, MSR1, and PALB2. Of clinical importance, in low incidence countries, the criteria used to define HDGC can be relaxed with little effect on mutation detection rates .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- van der Post RS, Vogelaar IP, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet 2015; 52:361.
- Oliveira C, Senz J, Kaurah P, et al. Germline CDH1 deletions in hereditary diffuse gastric cancer families. Hum Mol Genet 2009; 18:1545.
- Yamada H, Shinmura K, Ito H, et al. Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population. Cancer Sci 2011; 102:1782.
- Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 2010; 47:436.
- Hansford S, Kaurah P, Li-Chang H, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol 2015; 1:23.
- Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007; 297:2360.
- Oliveira C, Seruca R, Carneiro F. Genetics, pathology, and clinics of familial gastric cancer. Int J Surg Pathol 2006; 14:21.
- Benusiglio PR, Malka D, Rouleau E, et al. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J Med Genet 2013; 50:486.
- Yamada M, Fukagawa T, Nakajima T, et al. Hereditary diffuse gastric cancer in a Japanese family with a large deletion involving CDH1. Gastric Cancer 2014; 17:750.
- Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature 1998; 392:402.
- Keller G, Vogelsang H, Becker I, et al. Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation. Am J Pathol 1999; 155:337.
- Pharoah PD, Guilford P, Caldas C, International Gastric Cancer Linkage Consortium. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001; 121:1348.
- Blair V, Martin I, Shaw D, et al. Hereditary diffuse gastric cancer: diagnosis and management. Clin Gastroenterol Hepatol 2006; 4:262.
- Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 2004; 351:427.
- Guilford P, Blair V, More H, Humar B. A short guide to hereditary diffuse gastric cancer. Hered Cancer Clin Pract 2007; 5:183.
- Ford JM. Hereditary Gastric Cancer: An Update at 15 Years. JAMA Oncol 2015; 1:16.
- Richards FM, McKee SA, Rajpar MH, et al. Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum Mol Genet 1999; 8:607.
- 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 2004; 41:508.
- Hamilton LE, Jones K, Church N, Medlicott S. Synchronous appendiceal and intramucosal gastric signet ring cell carcinomas in an individual with CDH1-associated hereditary diffuse gastric carcinoma: a case report of a novel association and review of the literature. BMC Gastroenterol 2013; 13:114.
- Chun YS, Lindor NM, Smyrk TC, et al. Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? Cancer 2001; 92:181.
- Norton JA, Ham CM, Van Dam J, et al. CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann Surg 2007; 245:873.
- Suriano G, Yew S, Ferreira P, et al. Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management. Clin Cancer Res 2005; 11:5401.
- Park JG, Yang HK, Kim WH, et al. Report on the first meeting of the International Collaborative Group on Hereditary Gastric Cancer. J Natl Cancer Inst 2000; 92:1781.
- Lynch HT, Silva E, Wirtzfeld D, et al. Hereditary diffuse gastric cancer: prophylactic surgical oncology implications. Surg Clin North Am 2008; 88:759.
- Masciari S, Larsson N, Senz J, et al. Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet 2007; 44:726.
- Schrader KA, Masciari S, Boyd N, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer 2008; 7:73.
- Xie ZM, Li LS, Laquet C, et al. Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. Cancer 2011; 117:3112.
- Schrader KA, Masciari S, Boyd N, et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet 2011; 48:64.
- 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 2006; 43:138.
- Kluijt I, Siemerink EJ, Ausems MG, et al. CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling. Int J Cancer 2012; 131:367.
- Cisco RM, Ford JM, Norton JA. Hereditary diffuse gastric cancer: implications of genetic testing for screening and prophylactic surgery. Cancer 2008; 113:1850.
- Kaurah P, Fitzgerald R, Dwerryhouse S, Huntsman DG. Pregnancy after prophylactic total gastrectomy. Fam Cancer 2010; 9:331.
- Markman M. Principles of cancer screening. In: Cancer Screening: A Practical Guide for Physicians, Aziz K, Wu GY (Eds), Humana Press Inc, New Jersey 2002. p.3.
- Hamy A, Letessier E, Bizouarn P, et al. Study of survival and prognostic factors in patients undergoing resection for gastric linitis plastica: a review of 86 cases. Int Surg 1999; 84:337.
- Carneiro F, Huntsman DG, Smyrk TC, et al. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol 2004; 203:681.
- Barber ME, Save V, Carneiro F, et al. Histopathological and molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk. J Pathol 2008; 216:286.
- Lim YC, di Pietro M, O'Donovan M, et al. Prospective cohort study assessing outcomes of patients from families fulfilling criteria for hereditary diffuse gastric cancer undergoing endoscopic surveillance. Gastrointest Endosc 2014; 80:78.
- Barber M, Murrell A, Ito Y, et al. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol 2008; 216:295.
- Hebbard PC, Macmillan A, Huntsman D, et al. Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients. Ann Surg Oncol 2009; 16:1890.
- Huntsman DG, Carneiro F, Lewis FR, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med 2001; 344:1904.
- Caldas C, Carneiro F, Lynch HT, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet 1999; 36:873.
- Rogers WM, Dobo E, Norton JA, et al. Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol 2008; 32:799.
- Shaw D, Blair V, Framp A, et al. Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy? Gut 2005; 54:461.
- Chen Y, Kingham K, Ford JM, et al. A prospective study of total gastrectomy for CDH1-positive hereditary diffuse gastric cancer. Ann Surg Oncol 2011; 18:2594.
- van Kouwen MC, Drenth JP, Oyen WJ, et al. [18F]Fluoro-2-deoxy-D-glucose positron emission tomography detects gastric carcinoma in an early stage in an asymptomatic E-cadherin mutation carrier. Clin Cancer Res 2004; 10:6456.
- LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med 2014; 16:830.
- Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014; 32:2001.
- Johnston JJ, Rubinstein WS, Facio FM, et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet 2012; 91:97.
- Ricker C, Culver JO, Lowstuter K, et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Genet 2016; 209:130.
- Lowstuter K, Espenschied C, Sturgeon D, et al: Unexpected CDH1 mutations identified on multi-gene panels pose clinical management challenges. J Precis Oncol doi:10.1200/PO.16.00021.
- Ford JM. Totally Unexpected: Nonsyndromic CDH1 Mutations and Hereditary Diffuse Gastric Cancer Syndrome. JCO Precision Oncology 2017; 1:1.
- Lowstuter K, Espenschied CR, Sturgeon D, et al. Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges. JCO Precision Oncology 2017; 1:1.
- Shah MA, Salo-Mullen E, Stadler Z, et al. De novo CDH1 mutation in a family presenting with early-onset diffuse gastric cancer. Clin Genet 2012; 82:283.
- Sugimoto S, Yamada H, Takahashi M, et al. Early-onset diffuse gastric cancer associated with a de novo large genomic deletion of CDH1 gene. Gastric Cancer 2014; 17:745.
- MOLECULAR GENETICS
- RISK OF CANCER IN MUTATION CARRIERS
- Gastric cancer
- Other cancers
- IDENTIFICATION OF HIGH-RISK FAMILIES
- Genetic counseling and testing
- - Historical criteria for genetic testing
- Expanded criteria
- - Updated criteria for genetic testing
- - Performance of genetic testing
- MANAGEMENT OF MUTATION CARRIERS
- Prophylactic gastrectomy
- Endoscopic assessment for gastric cancer
- - HDGC endoscopic protocol
- - Chromoendoscopy
- Role of PET scan for individuals who refuse or delay surgery
- Management of CDH1 mutation carriers without typical HDGC syndrome
- Surveillance for breast and colorectal cancers
- SUMMARY AND RECOMMENDATIONS