Research Papers:
Comprehensive analysis of germline variants in mexican patients with hereditary breast and ovarian cancer susceptibility
Rosalía Quezada-Urban1, Clara Estela Díaz-Velásquez1, Rina Gitler2, María Patricia Rojo-Castillo2, Max Sirota-Toporek2, Andrea Figueroa-Morales2, Oscar Moreno-García2, Lizbeth García Esquivel2, Gabriela Torres-Mejía3, Michael Dean4, Iván Delgado-Enciso5, Héctor Ochoa-Díaz-López5, Fernando Rodriguez-León6, Virginia Jan7, Víctor Hugo Garzón-Barrientos8, Pablo Ruiz-Flores9, Perla Karina Espino-Silva9, Jorge Haro-Santa Cruz9, Héctor Martínez-Gregorio1, Ernesto Rojas-Jiménez1, Luis Enrique Romero Cruz1, Rosa María Álvarez-Gómez10, Verónica Fragoso Ontiveros10, Luis Alonso Herrera10, Isabelle Romieu11, Luis Ignacio Terrazas1, Yolanda Irasema Chirino1, Cecilia Frecha12, Javier Oliver12, Sandra Perdomo13,14 and Felipe Vaca-Paniagua1,10
1Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, México
2Fundación Alma, México
3Instituto Nacional de Salud Pública, México
4Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA
5Instituto Estatal de Cancerología de Colima, México
6Department of Health, El Colegio de la Frontera Sur (ECOSUR), San Cristóbal de Las Casas, Chiapas, México
7Internal Medicine, Hospital de Especialidades Vida Mejor, ISSTECH, Tuxtla Gutiérrez, Chiapas, Mexico
8Hospital General de Chilpancingo, Guerrero, México
9Centro de Investigación Biomédica Universidad Autónoma de Coahuila, México
10Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas-Instituto Nacional de Cancerología
11International Agency for Research on Cancer
12Hospital Italiano, Buenos Aires, Argentina
13Institute of Nutrition, Genetics and Metabolism Research, Faculty of Medicine, Universidad El Bosque, Bogotá, Colombia
14Department of Pathology and Laboratories, Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, Colombia
Correspondence to:
Felipe Vaca Paniagua, email: [email protected]
Keywords: genetic screening; hereditary breast cancer; massive parallel sequencing; gene panel; pathogenic variants
Received: January 10, 2018 Accepted: February 25, 2018 Published:
ABSTRACT
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant disease that represents 5–10% of all patients with breast cancer. This syndrome is mainly associated to high-risk pathogenic alleles in BRCA1 and BRCA2 genes, but only for 25% of HBOC cases. This work aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk individuals with a severe family history of cancer, using massive parallel sequencing. We found 15% (46/300) patients with pathogenic variants in the group of cancer patients; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had a 22% (6/27) of individuals with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Private or rare VUS with potential impact at protein level were found in 21 genes, being CHEK2 the one with most VUS (6/38). Noteworthy, our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%). This highlights the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to broader gene panels. Further studies are needed to define the clinical impact of the pathogenic alleles and VUS identified.