Abstract 4275: Pathogenic germline variants in Mexican patients with hereditary breast and ovarian cancer syndrome
Authors: Vaca-Paniagua Felipe , Quezada-Urban Rosalía , Díaz-Velásquez Clara , Gitler Rina , Torres-Mejia Gabriela , Rojo-Castillo Maria Patricia , Sirota-Toporek Max , Figueroa-Morales Andrea , Moreno-García Oscar , Delgado-Enciso Ivan , Garzón-Barrientos Victor Hugo , García-Esquivel Nayeli Lizbeth , Rojas-Jiménez Ernesto Arturo , Gregorio-Martínez Héctor , Terrazas Luis Ignacio 
Published: July 2017

Abstract
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant disease that represents approximately 5-10% of all patients with breast cancer. This syndrome is mainly associated to high risk pathogenic alleles in BRCA1/2 genes, but only for 25% of HBOC cases. More than 25 genes have been associated with familial breast and/or ovarian cancer and still more are expected to emerge. In the Mexican population there have been some efforts to analyze this syndrome, but they are limited to BRCA genes. This work aims to find new pathogenic alleles in exonic and splice sites in a panel of 143 cancer-predisposing genes in 309 Mexican cancer patients with suspicion of HBOC and 27 non-cancer patients with a severe family history of cancer, using massive parallel sequencing technology. In the group of cancer patients 14.6% (45/309) had pathogenic variants, 23.9% (74/309) harbored variants with unknown clinical significance (VUS) and 61.5% (109/309) were negative. The genes most frequently affected with pathogenic variants were BRCA2 24.4% (11/45), BRCA1 8.9% (4/45), MSR1 4.4% (2/45), ATM 4.4% (2/45), PDE11A 4.4% (2/45) and FANCI 4.4% (2/45). The non-cancer group had a 18.5% (5/27) of patients with pathogenic variants and 81.5% (22/27) were negative. In this group pathogenic variants were found in BRCA2, FANCF, PDE11A, POLH and WRN. Private or ultra-rare variants defined as VUS (ClinVar, deleterious in SIFT/Polyphen2, less than 0.001% in ExAC/1KG/ESP6500) were found in 53 genes. This study demonstrates that there is a higher contribution of pathogenic alleles in other susceptibility cancer genes (66.7%) than BRCA1/2 (33.3%), confirming that clinical sequencing of expanded gene panels will identify new, rare and private, variants and eventually will translate in better molecular diagnosis and personalized risk assessment in carriers. Clinical impact of the VUS identified here must be further evaluated. This work was supported by the National Autonomous University of Mexico, PAPIIT (IA204215).
Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara Díaz-Velásquez, Rina Gitler, Gabriela Torres-Mejia, Maria Patricia Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Ivan Delgado-Enciso, Victor Hugo Garzón-Barrientos, Nayeli Lizbeth García-Esquivel, Ernesto Arturo Rojas-Jiménez, Héctor Gregorio-Martínez, Luis Ignacio Terrazas. Pathogenic germline variants in Mexican patients with hereditary breast and ovarian cancer syndrome [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 4275. doi:10.1158/1538-7445.AM2017-4275