Abstract 1281: Identification of novel susceptibility genes in familial gastric cancer using next generation sequencing and identity-by-descent mapping
Authors: Sahasrabudhe Ruta M. , Lott Paul , Ruiz-Ponte Clara , Teixeira Manuel , Carvajal-Carmona Luis G. 
Published: May 2015

Abstract
Gastric cancer is the second most common cause of cancer related deaths worldwide, and approximately 10% of gastric cancer cases show familiar clustering of the disease. It is crucial to identify genes that predispose to familial gastric cancer because such families can undergo screening and cancer risk-reduction approaches, such as prophylactic gastrectomy. Furthermore, identification of new genes is also crucial to advance our understanding of the molecular basis of tumorigenesis. Till date, germline mutations in E-cadherin or CDH1 are the only known cause of Hereditary diffuse gastric cancer (HDGC), a form of familial gastric cancer syndrome. However, CDH1 mutations explain only a subset of familiar gastric cancer cases, indicating that many additional gastric cancer genes are still to be identified. Identification of cancer genes can be greatly facilitated if study samples are collected form isolated populations. These populations have simpler environments and genetic make-ups than that of large outbred groups and show larger founder effects, which allows easier and more tractable gene mapping that can later be portable in the worldwide population. In this study, we combine exome sequencing and identity by descent (IBD) analysis to identify novel, highly penetrant mutations in familial gastric cancer cases recruited in closely related and neighboring isolated populations from the Iberian Peninsula. We have already collected germline and tumor DNA samples from gastric cancer cases that belong to 32 families from the northwest regions of Portugal and Spain. All these cases and families are CDH1 mutation negative, and thus, potentially harbor mutations in unknown genes. We have completed exome sequencing of 16 of the index cases, and our preliminary data analysis has identified several interesting mutations that are in the phase of validation. Moving forward, we plan to complete exome sequencing of the remaining index cases as well as selected relatives from these families and validate mutations in a larger gastric cancer sample set. We will also be performing exome sequencing on tumor DNA that will enable us to identify loss of heterozygocity (LOH), as well as second hits and other molecular signatures in these tumor types. To our knowledge, our gene mapping effort in familial gastric cancer is one of the largest studies of its type, which can help identify novel gastric cancer genes and improve clinical management of gastric cancer cases.
Citation Format: Ruta M. Sahasrabudhe, Paul Lott, Clara Ruiz-Ponte, Manuel Teixeira, Luis G. Carvajal-Carmona. Identification of novel susceptibility genes in familial gastric cancer using next generation sequencing and identity-by-descent mapping. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1281. doi:10.1158/1538-7445.AM2014-1281