Origin and distribution of the BRCA2-8765delAG mutation in breast cancer

Grazia Palomba,Antonio Farris,Maria C Sini,Francesco Tanda,Marina Pisano,Giuseppe Palmieri,Antonio Cossu,Mario Budroni,Paola Baldinu,Antonio Contu,Eitan Friedman

doi:10.1186/1471-2407-7-132

Abstract

BackgroundThe BRCA2-8765delAG mutation was firstly described in breast cancer families from French-Canadian and Jewish-Yemenite populations; it was then reported as a founder mutation in Sardinian families. We evaluated both the prevalence of the BRCA2-8765delAG variant in Sardinia and the putative existence of a common ancestral origin through a haplotype analysis of breast cancer family members carrying such a mutation.MethodsEight polymorphic microsatellite markers (D13S1250, centromeric, to D13S267, telomeric) spanning the BRCA2 gene locus were used for the haplotype analysis. Screening for the 8765delAG mutation was performed by PCR-based amplification of BRCA2-exon 20, followed by automated sequencing.ResultsAmong families with high recurrence of breast cancer (≥ 3 cases in first-degree relatives), those from North Sardinia shared the same haplotype whereas the families from French Canadian and Jewish-Yemenite populations presented distinct genetic assets at the BRCA2 locus. Screening for the BRCA2-8765delAG variant among unselected and consecutively-collected breast cancer patients originating from the entire Sardinia revealed that such a mutation is present in the northern part of the island only [9/648 (1.4%) among cases from North Sardinia versus 0/493 among cases from South Sardinia].ConclusionThe BRCA2-8765delAG has an independent origin in geographically and ethnically distinct populations, acting as a founder mutation in North but not in South Sardinia. Since BRCA2-8765delAG occurs within a triplet repeat sequence of AGAGAG, our study further confirmed the existence of a mutational hot-spot at this genomic position (additional genetic factors within each single population might be involved in generating such a mutation).

Highlights

The BRCA2-8765delAG mutation was firstly described in breast cancer families from French-Canadian and Jewish-Yemenite populations; it was reported as a founder mutation in Sardinian families
Germline mutations in BRCA1 (MIM 113705) and BRCA2 (MIM 600185) genes account for cancer predisposition in majority of families with Breast Cancer (BC) recurrence
Positive family history is recognized as a high risk factor for developing the disease; about 10% of all breast cancers arise in individuals carrying a germline mutation in one of such two genes [1]

Summary

Introduction

The BRCA2-8765delAG mutation was firstly described in breast cancer families from French-Canadian and Jewish-Yemenite populations; it was reported as a founder mutation in Sardinian families. We evaluated both the prevalence of the BRCA2-8765delAG variant in Sardinia and the putative existence of a common ancestral origin through a haplotype analysis of breast cancer family members carrying such a mutation. According to the Breast Cancer Information Core (BIC) database [2], the majority of germline alterations identified in BRCA1 and BRCA2 is unique (57% and 63%, respectively); the remaining ones are recurrent founder mutations which have been described in different ethnic groups and populations [3]. BRCA1 and BRCA2 founder mutation have been detected in genetically homogeneous populations, such as the Icelanders [4,5], the Ashkenazi Jews [6], the Finns [7], and the French-Canadians [8]

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Conclusion