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

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.

A Mainly Circum-Mediterranean Origin for West Eurasian and North African mtDNAs in Puerto Rico with Strong Contributions from the Canary Islands and West Africa.

Maternal lineages of West Eurasian and North African origin account for 11.5% of total mitochondrial ancestry in Puerto Rico. Historical sources suggest that this ancestry arrived mostly from European migrations that took place during the four centuries of the Spanish colonization of Puerto Rico. This study analyzed 101 mitochondrial control region sequences and diagnostic coding region variants from a sample set randomly and systematically selected using a census-based sampling frame to be representative of the Puerto Rican population, with the goal of defining West Eurasian-North African maternal clades and estimating their possible geographical origin. Median-joining haplotype networks were constructed using hypervariable regions 1 and 2 sequences from various reference populations in search of shared haplotypes. A posterior probability analysis was performed to estimate the percentage of possible origins across wide geographic regions for the entire sample set and for the most common haplogroups on the island. Principal component analyses were conducted to place the Puerto Rican mtDNA set within the variation present among all reference populations. Our study shows that up to 38% of West Eurasian and North African mitochondrial ancestry in Puerto Rico most likely migrated from the Canary Islands. However, most of those haplotypes had previously migrated to the Canary Islands from elsewhere, and there are substantial contributions from various populations across the circum-Mediterranean region and from West African populations related to the modern Wolof and Serer peoples from Senegal and the nomad Fulani who extend up to Cameroon. In conclusion, the West Eurasian mitochondrial ancestry in Puerto Ricans is geographically diverse. However, haplotype diversity seems to be low, and frequencies have been shaped by population bottlenecks, migration waves, and random genetic drift. Consequently, approximately 47% of mtDNAs of West Eurasian and North African ancestry in Puerto Rico probably arrived early in its colonial history.

The spectrum of BRCA1 and BRCA2 alleles in Latin America and the Caribbean: a clinical perspective.

Hereditary cancer predisposition gene testing allows the identification of individuals at high risk of cancer that may benefit from increased surveillance, chemoprevention, and prophylactic surgery. In order to implement clinical genetic strategies adapted to each population's needs and intrinsic genetic characteristic, this review aims to present the current status of knowledge about the spectrum of BRCA pathogenic variants in Latin American populations. We have conducted a comprehensive review of 33 studies published between 1994 and 2015 reporting the prevalence and/or spectrum of BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) variants. The combined sample size for these studies consisted of 4835 individuals from 13 countries in Latin America and the Caribbean, as well as in Hispanics in the United States. A total of 167 unique pathogenic variants have been reported in the existing literature. In unselected breast cancer cases, the prevalence ranged from 1.2 to 27.1%. Some countries presented a few recurrent pathogenic variants, while others were characterized by diverse, non-recurrent variants. The proportion of BRCA pathogenic variants shared between Hispanics in the United States and Latin American populations was estimated at 10.4%. Within Latin America and the Caribbean, 8.2% of the BRCA variants reported were present in more than one country. Countries with high prevalence of BRCA pathogenic variants may benefit from more aggressive testing strategies, while testing of recurrent variant panels might present a cost-effective solution for improving genetic testing in some, but not all, countries.