A systematic review of the indications for genetic testing and prophylactic gastrectomy among patients with hereditary diffuse gastric cancer

Abstract

Background Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome specifically associated with germline mutations to the E-cadherin (CDH1) gene. HDGC is characterized by autosomal dominance and high penetrance and a high cumulative risk for advanced gastric cancer. Our purpose in this study was to identify and synthesize findings from all articles on: (1) current recommendations for CDH1 screening and prophylactic gastrectomy; (2) CDH1 testing results in HDGC patients; and (3) prophylactic gastrectomy results in HDGC patients. Methods Systematic electronic literature searches were conducted using Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1985 to 2009. Results Seventy articles were included in this review. Among patients with a positive family history of gastric cancer, 1085 were screened from 454 families, and 38.4% tested positive. Mutation-positive families also had a considerable family history of breast and colon cancer. Of the 322 patients screened for CDH1 mutations by current HDGC screening criteria, 29.2% tested positive. Among the 76.8% of patients who underwent prophylactic gastrectomy following positive CDH1 test results, 87.0% had positive final histopathology results and 64.6% had signet ring cells identified. Some of the patients with negative final histopathology results had opted to undergo prophylactic gastrectomy prior to CDH1 testing, and were ultimately found to be negative for CDH1 mutations. Conclusion CDH1 mutation testing in families with a history of gastric cancer and prophylactic gastrectomy in mutation-positive patients are recommended for the management of HDGC.

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

“…CDH1 mutations occur in 25-50% of individuals who meet the hereditary diffuse gastric cancer criteria. 72 The International Gastric Cancer Linkage Consortium's most recent consensus guidelines for the clinical management of hereditary diffuse gastric cancer include indications for CDH1 testing and have been adopted below. 73 Referral should be considered for any individual with a personal history of or first-degree relative with (i) diffuse gastric cancer diagnosed before age 40; (ii) lobular breast cancer and diffuse gastric cancer in the same person; (iii) lobular breast cancer in one relative and diffuse gastric cancer in another, one diagnosed before age 50; or (iv) two cases of gastric cancer in family, one of which is a confirmed diffuse gastric cancer diagnosed before age 50.…”

Clinical epidemiology of gastric cancer

“…In this rare disorder, CDH1 mutation testing in families with a history of gastric cancer and prophylactic gastrectomy in mutation-positive patients are recommended for management. (70) HOST GENETIC POLYMORPHISMS AND GASTRIC CANCER RISK Host genetic polymorphisms may have an impact on host responses to gastric inflammation and acid secretion, thereby interacting with H. pylori infection in gastric carcinogenesis. A series of single nucleotide polymorphisms (SNPs) of susceptibility genes have been implicated.…”

Mainstreaming genetic testing of cancer predisposition genes

“…Prevention usually involves surgical removal of the at-risk tissue and is necessarily reserved for nonessential organs in individuals at very high-risk, such as the stomach in CDH1 mutation carriers, the thyroid in RET mutation carriers and the breast and ovaries in BRCA1 mutation carriers. [14][15][16] Chemoprevention is an attractive strategy, but to date there have been few applications. A notable exception is individuals with increased risk of colorectal cancer in whom the cancer risk is signifi cantly reduced by daily aspirin.…”