Abstract LB-158: Germline mutations in <i>PALB2</i>, <i>BRCA1</i> and <i>RAD51C</i> observed in gastric cancer cases
Authors: Ruta Sahasrabudhe, Paul Lott, Mabel Bohorquez, Ted Toal, Ana Estrada, John Suarez, Alejandro Brea-Fernández, Jose Cameselle-Teijeiro, Carla Pinto, Irma Ramos, Alejandra Mantilla, Rodrigo Prieto, Alejandro Corvalan, Enrique Norero, Carolina Alvarez, Teresa Tapia, Pilar Carvallo, Luz Gonzalez, Alicia Cock-Rada, Angela Solano, Florencia Neffa, Adriana Della Valle, Chris Yau, Gabriela Soares, Alexander Borowsky, Xiao-You Han, Li-JI He, Phillip Taylor, Alisa Goldstein, Nan Hu, Javier Torres, Magdalena Echeverry, Clara Ruiz-Ponte, Manuel Teixeira, Luis G. Carvajal-Carmona
Journal: Cancer Research (2017)

Abstract Gastric cancer (GC) is the third common cause of cancer related deaths worldwide and its risk is partially mediated by inherited factors. However, the majority of GC heritability remains to be discovered. The goal of this study was to identify novel GC genes. To identify novel GC genes, we undertook a multi-staged approach of whole exome sequencing (WES), followed by targeted sequencing and genotyping in germline DNA samples from hereditary diffuse GC (HDGC) and isolated GC cases recruited in Europe and Latin America. We also performed WES in 4 available tumor samples to analyze loss of heterozygosity and somatic mutation signature. Our study identified eleven cases with mutations in homologous recombination repair (HR) genes, including seven with PALB2 mutations, three with BRCA1 mutations and one with a RAD51C mutation. Out of 361 total unrelated GC cases analyzed, 6.45% of the HDGC cases (2 out of 31) and 2.7% (9 out of 330) of isolated/non-HDGC cases had mutations in PALB2, BRCA1 or RAD51C. Most of these mutations are known as pathogenic in other cancer types and three were shared by multiple Hispanic and European cases. None of these mutations were present in 1,170 population-matched controls (P=5.75x10-7). Tumor samples from four mutation carriers exhibited mutational signature indicative of defects in HR pathway. Our results suggest that mutations in HR genes are likely involved in GC susceptibility. Our findings have potential clinical implications as these cases and their families could benefit from risk reducing surveillance and possibly benefit from platinum or PARP inhibitor based therapies. Citation Format: Ruta Sahasrabudhe, Paul Lott, Mabel Bohorquez, Ted Toal, Ana Estrada, John Suarez, Alejandro Brea-Fernández, Jose Cameselle-Teijeiro, Carla Pinto, Irma Ramos, Alejandra Mantilla, Rodrigo Prieto, Alejandro Corvalan, Enrique Norero, Carolina Alvarez, Teresa Tapia, Pilar Carvallo, Luz Gonzalez, Alicia Cock-Rada, Angela Solano, Florencia Neffa, Adriana Della Valle, Chris Yau, Gabriela Soares, Alexander Borowsky, Xiao-You Han, Li-JI He, Phillip Taylor, Alisa Goldstein, Nan Hu, Javier Torres, Magdalena Echeverry, Clara Ruiz-Ponte, Manuel Teixeira, Luis G. Carvajal-Carmona. Germline mutations in PALB2, BRCA1 and RAD51C observed in gastric cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-158. doi:10.1158/1538-7445.AM2017-LB-158