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

Nelly Arroyo,Michael Dean,Cynthia Perez,Edna Mora,Taras Oleksyk,Hector Diaz-Zabala,Julie Dutil,Lisa Garland,Miguel Echenique,Kristine Jones,Jaime Matta,Ana Ortiz

doi:10.3390/cancers10110419

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.

Highlights

Pathogenic variants in the highly penetrant susceptibility genes BRCA1 and BRCA2 confer an increased lifetime risk of breast, ovarian and other cancers [1,2]
Our preliminary work indicates that at least 8.3% of the high-risk breast cancer (BC) patients for which no BRCA mutation is identified carry a pathogenic variant in another susceptibility gene [44]
Compared to our previous work in Puerto Rico, this study presents the advantage of screening for BRCA mutations in a larger sample of BC patients that have not been selected for family history or age of onset

Summary

Introduction

Pathogenic variants in the highly penetrant susceptibility genes BRCA1 and BRCA2 confer an increased lifetime risk of breast, ovarian and other cancers [1,2]. While most populations of Latin America and the Caribbean result from the admixture of ancestors from African, European and Native American origins, substantial heterogeneity has been observed within and across countries [11]. Such variability translates into distinct genetic architecture underlying diseases with a hereditary component. The prevalence of hereditary cancers attributed to pathogenic variants in the BRCA1 and BRCA2 genes in unselected BC patients from Latin America and the Caribbean varies from 1.2% in Columbia to 27.1% in the Bahamas [12]. As a result of founder effects, some populations have shown decreased genetic variability in the spectrum of BRCA mutations observed, but others such as Argentina exhibit considerable diversity with fewer recurrent mutations [12]

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