Abstract 2739: Transcontinental characterization of the Hispanic BRCA1 3450del4 breast cancer founder mutation
Authors: Tuazon Anna Marie De Asis , Ramirez Carolina , Bohorquez Mabel , Prieto Rodrigo , Lott Paul , Criollo Angel , Estrada Ana , Mateus Gillbert , Velez Alejandro , Ramirez Justo ,   COLUMBUS Consortium, Teixeira Manuel , Vega Ana , Lazaro Conxi , Tornero Eva , Martinez Cristina , Infante Mar , De La Hoya Miguel , Diez Orland , Carvallo Pilar , Echeverry Magdalena , Carvajal-Carmona Luis 
Published: August 2015

Breast cancer (BC) is the most commonly diagnosed cancer among women, with 1 in every 7 women in the U.S. developing BC in their lifetime. While BC may not be the leading cause of cancer incidence in many minority populations, such as Hispanics, it is the leading cause of cancer death, highlighting a cancer disparity. Moreover, the contribution of mutations in BC susceptibility genes remains poorly investigated in Hispanic populations. To begin to address these voids, we screened Colombian BC patients for common BRCA1 and BRCA2 mutations using the KASP genotyping system. Strikingly, 27 of 722 unselected cases (4%) harbored the same BRCA1 3450del4 mutation. Clinical data and family history indicate that these individuals originate from a distinct geographic region in Colombia, Neiva. Significantly, 10% of the unselected BC cases in Neiva and the surrounding region harbor the 3450del4 mutation, potentially representing one of the most profound founder effects reported in human populations. Interesting, this BRCA1 mutation has also been reported in other countries, including Portugal, Spain, and Chile. To determine whether this mutation stems from a single origin, mutation carriers from each of these countries (n = 26), along with mutation carriers from Colombia (n = 27), were subjected to the Affymetrix Axiom Human UK Biobank Array (&gt;800 thousand markers). Haplotypes in which the BRCA1 mutation resides were estimated by SHAPEIT, and pairwise segmental sharing was determined using GERMLINE. Our data suggest that the mutation carriers, although from different countries and continents, share a core haplotype, likely to have originated from Spain. Additionally, the mutation seems to be fairly new to Colombia, with individuals sharing up to a 40Mb haplotype comprising the mutation. We are currently estimating the age of the mutation using the bioinformatic software DMLE+, which exploits the rate of linkage disequilibrium decay due to recombination. By understanding the prevalence of mutations in known breast cancer risk genes in minority populations, cancer disparities can be better addressed and breast cancer screening can be improved. Furthermore, these findings have direct implications in robust and cost-effective targeted screening in regions where there is a high prevalence of the BRCA1 3450del4 mutation.

Citation Format: Anna Marie De Asis Tuazon, Carolina Ramirez, Mabel Bohorquez, Rodrigo Prieto, Paul Lott, Angel Criollo, Ana Estrada, Gillbert Mateus, Alejandro Velez, Justo Ramirez, COLUMBUS Consortium, Manuel Teixeira, Ana Vega, Conxi Lazaro, Eva Tornero, Cristina Martinez, Mar Infante, Miguel De La Hoya, Orland Diez, Pilar Carvallo, Magdalena Echeverry, Luis Carvajal-Carmona. Transcontinental characterization of the Hispanic BRCA1 3450del4 breast cancer founder mutation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2739. doi:10.1158/1538-7445.AM2015-2739