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Hereditary diffuse gastric cancer

Debrah Wirtzfeld, MD, MSc, FRCSC, FACS
Kasmintan A Schrader, MBBS, FRCPC, PhD
David Huntsman, MD, FRCPC, FCCMG
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD


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) [1]. (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 [2] and lower in moderate-incidence countries like Germany (25 percent), and lowest in high-incidence countries like Portugal and Italy (22.2 percent) [2] and Japan (15.4 percent) [3]. A more recent series of 183 index cases meeting the 2010 IGCLC clinical criteria for CDH1 testing [4] from Canada, Portugal, and Italy reported a lower than expected detection rate for a pathogenic CDH1 mutation (19 percent) [5]. 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 [6].


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Literature review current through: Sep 2016. | This topic last updated: May 9, 2016.
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