Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach

Abstract

Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ∼5-10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment Oliver et al. Latin American HBOC Study of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations.

Germline mutations in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer

“…However, this mutation was not seen in the given to BRCA1 mutations c.212+1G>A and BRCA1 c.799delT, which were the most prevalent within our study population. These two mutations were also seen once each in the 19 Guatemalan patients included in Oliver et al [6]. To the best of our knowledge, this is the largest genetic study of Central American breast cancer.…”

“…documented that Latin American women referred for genetic testing have equal or higher rates of BRCA1 and BRCA2 mutations (15%) as other groups [4]. The frequency and spectrum of hereditary cancer gene mutations have been described in Latin American and US Hispanic populations [5][6][7][8]. However, cancer disparities among US Hispanic subgroups may be further masked because they tend to be aggregated as a monolithic group in epidemiological studies.…”

Germline mutations in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer

“…In our study of 664 breast cancer patients from Guatemala, 11% (73/664) were found to carry pathogenic mutations in high and medium penetrance breast cancer susceptibility genes. Guatemalan women have a higher ratio of deleterious BRCA1/BRCA2 mutations (2.8) than US Hispanic women or other Latin American populations [3][4][5][6]. The higher BRCA1 mutation rate is attributable to the high prevalence of the c.212 + 1G > A and c.799delT mutations.…”

“…These two mutations are not known to be common in the United States and other Latin American countries, suggesting that they are founder mutations in the Guatemalan population [3,6,8]. A previous study of 222 patients across four Latin American countries (Argentina, Colombia, Guatemala, and Mexico) had described a prevalence of pathogenic variants at 17% (38/222); however, if only high and medium penetrance breast cancer genes are included that percentage drops to 13% (29/222) overall and 11% (2/19) in Guatemala [6]. The BRCA mutation prevalence among Latinas in the US is 1.2-4.9% in cohorts of unselected patients with breast cancer and a separate study of 1054…”

“…Genetic testing for germline mutations in breast cancer susceptibility genes can identify individuals with a higher risk of developing breast cancer, but there is limited information on the mutation pro le of many Latin American populations [2,3] Hall et al documented that Latin American women referred for genetic testing have equal or higher rates of BRCA1 and BRCA2 mutations (15%) as other groups [4]. The frequency and spectrum of hereditary cancer gene mutations have been described in Latin American and US Hispanic populations [5][6][7][8]. However, cancer disparities among US Hispanic subgroups may be further masked because they tend to be aggregated as a monolithic group in epidemiological studies.…”