A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico

Abstract

Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States.

Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

“…The high proportion of AJ individuals in our cohort (14.0%) contributed to the high overall prevalence observed. Multiple other founder variants were also detected in different populations in our study, including the c.3922G>T (p.Glu1308Ter) variant in BRCA2 that we found in almost half of the variant positive individuals with ancestry from PR, consistent with previous findings (32). We report, for the first time, prevalence estimates in a number of diverse populations, including African American and Hispanic/Latino populations for which these estimates did not previously exist.…”

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.…”

“…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.…”

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 E1308X in Puerto Rico [3,5,7]. One recurrent mutation that has been documented in several populations across Latin America and US Hispanics is the Jewish founder mutation BRCA1 185delAG [4,28].…”

“…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.…”