A role of BRCA1 and BRCA2germline mutations in breast cancer susceptibility within Sardinian population

Grazia Palomba,Laura Crisponi,Marina Pisano,Giovanna Piras,Maria Monne,Giuseppe Palmieri,Antonella Uras,Patrizia Fancello,Mario Lovicu,Angela Loi,Attilio Gabbas,Maria Cristina Santona,Gennaro Landriscina,Antonio Cossu,Francesco Tanda,Mario Budroni,Sandra Orrù,A Contu ,C Floris ,A Farris

doi:10.1186/1471-2407-9-245

Abstract

BackgroundIn recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated.MethodsThree hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test.Results and ConclusionOverall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764_8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations.

Highlights

In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts
Screening for BRCA1 and BRCA2 mutations Genomic DNA from 348 probands of breast-ovarian cancer families was screened for germline mutations in
Presence of ovarian cancer in family increased the occurrence of BRCA1-2 germline mutations in either the subset of "high-risk" families (5/16; 31%) or the group of "no high-risk" families (1/8; 12.5%)

Summary

Introduction

Numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. Familial aggregation is thought to account for 5–10% of all breast cancer cases, and germline mutations in different genes involved in pathways critical to maintain the genomic integrity have accounted for less than 25% of the inherited breast cancer [3,4]. Part of this familial clustering shows autosomal dominant inheritance with high penetrance due to mutations in the BRCA1 (MIM 113705) and BRCA2 (MIM 600185) breast cancer genes [5,6]. Women with BRCA mutations are at significant risk to develop ovarian cancer and other malignancies [7]

Methods

Results

Discussion

Conclusion