Gastric Cancer: A Multidisciplinary Approach

The correct answer is the 2nd option. Mutations of CDH1, the gene encoding E-cadherin, are the most common germline mutations that underlie hereditary diffuse gastric cancer (HDGC) syndrome. CDH1 germline mutations also increase the risk of lobular breast cancer and are associated with blepharocheilodontic syndrome (a developmental disorder). CDH1, the coding gene for E-cadherin, is located on chromosome 16q22.1 and consists of 16 exons. More than 100 CDH1 pathogenic variants, with considerable variation in clinical manifestations, have been described in HDGC families. The reported HDGCs are the pure diffuse type by Lauren classification and associated with dismal prognosis once the tumor invades the submucosa. Studies suggest that HDGC progresses through several stages, and even when the tumor invades the lamina propria, it may stay indolent for a long time. Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have a high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate screening for CDH1 mutation carriers; these criteria are proven with high sensitivity and predictive value. Of note, germline CDH1 mutations may not be detectable in patients who meet the HDGC criteria. Families without recognized inactivating CDH1 mutations may have undisclosed mutations in CDH1 or in its regulatory sequences or germline mutations in unidentified genes. CDH1 promoter hypermethylation also seems a key event in the carcinogenetic process. Although MSH2, APC and STK11 aberrancies are associated with developing gastric cancer (in the context of LS, FAP and PJS, respectively), in setting of HDGC and lobular breast cancer, the second option (CDH1 aberrations) is the most accurate response. 

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