Deletion of Chromosomes 13q and 14q Is a Common Feature of Tumors with BRCA2 Mutations

Audrey Rouault,Nabila Elarouci,Guillaume Banneau,Aurélien De Reyniès,Gaëtan Macgrogan,Natalie Jones,Laurence Venat,Richard Iggo,Isabelle Coupier,Nicolas Sévenet,Emmanuelle Barouk-Simonet,Eric Letouzé,Françoise Bonnet,Michel Longy,Sandra Orsulic

doi:10.1371/journal.pone.0052079

Abstract

IntroductionGermline BRCA1 or BRCA2 mutations account for 20–30% of familial clustering of breast cancer. The main indication for BRCA2 screening is currently the family history but the yield of mutations identified in patients selected this way is low.MethodsTo develop more efficient approaches to screening we have compared the gene expression and genomic profiles of BRCA2-mutant breast tumors with those of breast tumors lacking BRCA1 or BRCA2 mutations.ResultsWe identified a group of 66 genes showing differential expression in our training set of 7 BRCA2-mutant tumors and in an independent validation set of 19 BRCA2-mutant tumors. The differentially expressed genes include a prominent cluster of genes from chromosomes 13 and 14 whose expression is reduced. Gene set enrichment analysis confirmed that genes in specific bands on 13q and 14q showed significantly reduced expression, suggesting that the affected bands may be preferentially deleted in BRCA2-mutant tumors. Genomic profiling showed that the BRCA2-mutant tumors indeed harbor deletions on chromosomes 13q and 14q. To exploit this information we have created a simple fluorescence in situ hybridization (FISH) test and shown that it detects tumors with deletions on chromosomes 13q and 14q.ConclusionTogether with previous reports, this establishes that deletions on chromosomes 13q and 14q are a hallmark of BRCA2-mutant tumors. We propose that FISH to detect these deletions would be an efficient and cost-effective first screening step to identify potential BRCA2-mutation carriers among breast cancer patients without a family history of breast cancer.

Highlights

Germline breast cancer 1 (BRCA1) or BRCA2 mutations account for 20–30% of familial clustering of breast cancer
To gain insight into the biology of BRCA2-mutant breast tumors, we performed a supervised analysis looking for genes differentially expressed in BRCA2-mutant and control tumors
All of the tumors came from patients with a familial clustering of breast cancer potentially caused by germline mutation of a breast cancer predisposition gene

Summary

Introduction

Germline BRCA1 or BRCA2 mutations account for 20–30% of familial clustering of breast cancer. Germline mutations in pathways critical for maintenance of genomic integrity confer an increased risk of developing breast cancer [1]. Consistent with the Knudson two-hit model, both alleles of BRCA1 and BRCA2 are inactivated in tumors, indicating that the genes behave like classic tumor suppressor genes [3]. Their gene products are implicated in the repair of DNA double-strand breaks [4]: BRCA1 is required for recruitment of repair proteins to sites of breakage [5], whereas. Loss of these functions leads to genomic instability [7].

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Conclusion