Abstract P3-07-05: Frequent BRCA1 and BRCA2 mutations are found in Mexican and Mexican-American women with breast cancer

Abstract

Background: The Arizona Cancer Registry has shown that in Pima County, AZ, breast cancer diagnosed in young Latinas increased 40% from 2004-2008, compared to 1999-2003, and Latinas more likely to die of their cancer. This study seeks to characterize genetic variation in women of Mexican ancestry with breast cancer using next generation sequencing, with the goal of providing prevalence information to help guide screening and cancer prevention efforts. Methods: The ELLA Binational Breast Cancer Study enrolled women of Mexican ancestry living in either U.S. or Mexico within 24 months of breast cancer diagnosis. Mexican women from the state of Jalisco were collected through collaboration with the Universidad de Guadalajara and women of Mexican ancestry were recruited from Tucson and Phoenix, AZ. Genomic DNA from 92 ELLA study participants (49 from the U.S. and 43 from Mexico) was enriched for breast cancer influencing gene sequence using the BROCA panel with standard techniques. Samples were sequenced with next generation sequencing and variants identified. Results: Sequencing of breast cancer risk genes in 92 Mexican and Mexican-American women with breast cancer revealed the presence of deleterious mutations in 15% of women (14/92). Five carry mutations in BRCA1, 5 in BRCA2, 2 in CHEK2, 1 in PALB2 and 1 in RAD51C. An additional 9% of participants (8/92) carry rare mutations of unknown functional consequence in the same genes. Four carry mutations in BRCA1 or BRCA2 at sites predicted to alter splice enhancers and four carry missense mutations in CHEK2 that are predicted to damage to kinase function. None of these variants appear in public databases or are characterized functionally in gene-specific databases. Dozens of women carry VUS or novel variants. Women carrying BRCA1 mutations are significantly more likely to have had triple negative pathology. Women carrying other mutations known or thought to be deleterious are also more likely to have been younger at diagnosis, to have more aggressive breast cancer or to report a family history of breast cancer. Table 1. Deleterious MutationsGeneEffectTotalBRCA1185delAG1BRCA12569delC2BRCA1Del Complete Gene1BRCA1Del Exons 9-121BRCA2c.658delGT1BRCA2c.3264insT2BRCA2c.5195delT1BRCA2c.6024insG1CHEK2R160G2PALB2S779 Stop1RAD51CDel Exons 4-91 Conclusion: Deleterious BRCA1 and BRCA2 gene mutations are common among women of Mexican ancestry diagnosed with breast cancer. Within this cohort, the prevalence of BRCA1/2 mutations is 11%, and 4% of women carry mutations in other genes increasing breast cancer risk. This is higher than the 10% mutation prevalence estimated for Ashkenazi Jewish women with breast cancer. An additional 9% of women carry variants likely to disrupt gene function and dozens of VUS and novel variants are found in these women. Further analysis of samples from the remaining 942 women using genetic sequencing will help further elucidate the role of genetic risk factors in women of Mexican ancestry with breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-05.