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Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility

1
Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, Estado de México 54090, Mexico
2
Fundación Alma, CDMX 11560, Mexico
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Instituto Nacional de Salud Pública, 62100 Cuernavaca, Morelos, Mexico
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Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
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Instituto Estatal de Cancerología de Colima, Colima 28000, Colima, Mexico
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Department of Health, El Colegio de la Frontera Sur (ECOSUR), San Cristóbal de Las Casas 29290, Chiapas, Mexico
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Internal Medicine, Hospital de Especialidades Vida Mejor, ISSTECH, Tuxtla Gutiérrez 29040, Chiapas, Mexico
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Hospital General de Chilpancingo, Chilpancingo de los Bravo 39019, Guerrero, Mexico
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Centro de Investigación Biomédica, Universidad Autónoma de Coahuila, Torreón 27000, Coahuila, Mexico
10
Instituto Nacional de Cancerología, CDMX 14080, Mexico
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Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas-Instituto Nacional de Cancerología, CDMX 14080, Mexico
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Center for Center for Research on Population Health, National Institute of Public Health, Cuernavaca 62100, Morelos, Mexico
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Hubert Department of Global Health, Emory University, Atlanta, GA 30322, USA
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Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, 54090 Tlalnepantla, Estado de México, Mexico
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Hospital Italiano, Buenos Aires C1199ABB, Argentina
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Investigación en Nutrición, Genética y Metabolismo, Facultad de Medicina, Universidad El Bosque, Bogotá 110121, Colombia
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Department of Pathology and Laboratories, Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá 110100, Colombia
*
Author to whom correspondence should be addressed.
Cancers 2018, 10(10), 361; https://doi.org/10.3390/cancers10100361
Received: 3 August 2018 / Revised: 5 September 2018 / Accepted: 15 September 2018 / Published: 27 September 2018
Hereditary breast and ovarian cancer syndrome (HBOC) represents 5–10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We 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 patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients 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. Rare VUS with potential impact at the protein level were found in 21 genes. 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%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels. View Full-Text
Keywords: BRCA1/2; genetic screening; hereditary breast cancer; massive parallel sequencing; gene panel; pathogenic variants BRCA1/2; genetic screening; hereditary breast cancer; massive parallel sequencing; gene panel; pathogenic variants
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Quezada Urban, R.; Díaz Velásquez, C.E.; Gitler, R.; Rojo Castillo, M.P.; Sirota Toporek, M.; Figueroa Morales, A.; Moreno García, O.; García Esquivel, L.; Torres Mejía, G.; Dean, M.; Delgado Enciso, I.; Ochoa Díaz López, H.; Rodríguez León, F.; Jan, V.; Garzón Barrientos, V.H.; Ruiz Flores, P.; Espino Silva, P.K.; Haro Santa Cruz, J.; Martínez Gregorio, H.; Rojas Jiménez, E.A.; Romero Cruz, L.E.; Méndez Catalá, C.F.; Álvarez Gómez, R.M.; Fragoso Ontiveros, V.; Herrera, L.A.; Romieu, I.; Terrazas, L.I.; Chirino, Y.I.; Frecha, C.; Oliver, J.; Perdomo, S.; Vaca Paniagua, F. Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility. Cancers 2018, 10, 361.

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