Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy

Abstract

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes are present in about 50% of cases of hereditary breast cancer. Proteins encoded by these genes are key players in DNA repair by homologous recombination (HR). Advances in next generation sequencing and gene panels for breast cancer testing have generated a large amount of data on gene variants implicated in hereditary breast cancer, particularly in genes such as PALB2, ATM, CHEK2, RAD51, MSH2, and BARD1. These genes are involved in DNA repair. Most of these variants have been reported for Caucasian, Jewish, and Asian population, with few reports for other communities, like those in Latin American (LA) countries. We reviewed 81 studies from 11 LA countries published between 2000 and 2019 but most of these studies focused on BRCA1/2 genes. In addition to these genes, breast cancer-related variants have been reported for PALB2, ATM, CHEK2, BARD1, MLH1, BRIP1, MSH2, NBN, MSH6, and PMS2 genes. Some of these variants are unique to LA populations. This analysis may contribute to enhance breast cancer variant characterization, and thus to find therapies and implement precision medicine for LA communities.

Identification of Variants (rs11571707, rs144848, and rs11571769) in the BRCA2 Gene Associated with Hereditary Breast Cancer in Indigenous Populations of the Brazilian Amazon

“…The Amerindians from the Amazon region have a unique genetic profile because of stochastic processes resulting from a long process of geographic isolation and inbreeding [ 42 ]. Additionally, some small groups migrated from settled areas to uninhabited territories, giving rise to the first indigenous communities [ 36 ].…”

Double heterozygous pathogenic variants in the BRCA1 and BRCA2 genes in a patient with bilateral metachronous breast cancer: a case report

“…These two pathogenic variants have not been described together so far [3]. There are few reports of double heterozygosity variants in BRCA1 and BRCA2 genes in Latin America [7]. A woman with double heterozygosity variants was previously reported in Argentina but the patient developed breast and ovarian cancer and has a large rearrangement mutation in BRCA1 gene and a splicing mutation in BRCA2 gene [12].…”

“…It is a prevalent founder mutation in the Central Spain region, accounting for 13.6% of BRCA2 positive families [10]. In Latinoamerica, it was reported in two ovarian cancer patients from Argentina [12] and in breast cancer families from Chile [7,11,18]. The BRCA2 pathogenic variant was located inside ovarian cancer cluster region (OCCR) which is associated with a lower breast cancer risk compared with mutations outside the OCCR (c.2831-c.6401) [13].…”

“…Few reviews describe the status of BRCA1 or BRCA2 variants in women from Latin America and the Caribbean [4][5][6][7]. In Argentina, Solano et al reported low frequency of recurrent mutations in BRCA1 or BRCA2 genes, probably because the population has an admixture of European ancestry -mainly from Spain and Italy-and an Amerindian component [8].…”

Sequencing technology status of BRCA1/2 testing in Latin American Countries

“…The collection and documentation of regional genetic variants are valuable in order to understand the genetic landscape of the region, which is under-represented in many United States or European variant databases. This information is critical as novel genetic variants are very frequently detected in most Latin American countries, and there may be regional founder pathogenic variants or common polymorphisms [6][7][8][9][10][11][12][13][14][15][16] .…”