Hereditary Diffuse Gastric Cancer Syndrome
Authors: Samantha Hansford, Pardeep Kaurah, Hector Li-Chang, Michelle Woo, Janine Senz, Hugo Pinheiro, Kasmintan A. Schrader, David F. Schaeffer, Karey Shumansky, George Zogopoulos, Teresa Almeida Santos, Isabel Claro, Joana Carvalho, Cydney Nielsen, Sarah Padilla, Amy Lum, Aline Talhouk, Katie Baker-Lange, Sue Richardson, Ivy Lewis, Noralane M. Lindor, Erin Pennell, Andree MacMillan, Bridget Fernandez, Gisella Keller, Henry Lynch, Sohrab P. Shah, Parry Guilford, Steven Gallinger, Giovanni Corso, Franco Roviello, Carlos Caldas, Carla Oliveira, Paul D. P. Pharoah, David G. Huntsman
Journal: JAMA Oncology (2015)

<h3>Importance</h3> E-cadherin (<i>CDH1</i>) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without<i>CDH1</i>mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. <h3>Objectives</h3> To derive accurate estimates of gastric and breast cancer risks in<i>CDH1</i>mutation carriers and determine if germline mutations in other genes are associated with HDGC. <h3>Design, Setting, and Participants</h3> Testing for<i>CDH1</i>germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking<i>CDH1</i>mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. <h3>Main Outcomes and Measures</h3> Accurate estimates of gastric and breast cancer risks in<i>CDH1</i>mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. <h3>Results</h3> Thirty-one distinct pathogenic<i>CDH1</i>mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In<i>CDH1</i>mutation–negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance:<i>CTNNA1</i>,<i> BRCA2</i>,<i> STK11</i>,<i> SDHB</i>,<i> PRSS1</i>,<i>ATM</i>,<i> MSR1</i>, and<i>PALB2</i>. <h3>Conclusions and Relevance</h3> This is the largest reported series of<i>CDH1</i>mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking<i>CDH1</i>mutations, testing of<i>CTNNA1</i>and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie,<i>BRCA2)</i>with different clinical ramifications from<i>CDH1</i>. Therefore, we propose that HDGC syndrome may be best defined by mutations in<i>CDH1</i>and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.