Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion

Amanda Gonçalves Silva,Amanda França De Nóbrega,Carla Rosenberg,Ana C V Krepischi,Dirce M Carraro,Ingrid Petroni Ewald,Patricia Ashton-Prolla,Manuela Pinheiro,Maria Isabel W Achatz,Manuel R Teixeira,Ana Peixoto,Marina Sapienza

doi:10.1186/1471-2407-12-237

Abstract

BackgroundLi-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype.MethodsWe have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes.ResultsWe found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences.ConclusionThis is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility.

Highlights

Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors
Germline mutations of the tumor suppressor gene TP53 account for more than half of the families with classic Li-Fraumeni syndrome (LFS) [1], which is an inherited condition characterized by the development of sarcomas and other early-onset tumors, including breast cancer [2,3]
Germline mutations of the BRCA2 gene have been described in families presenting both breast cancer and sarcomas, suggesting that BRCA2 mutations account for a proportion of LFS/LFL families negative for TP53 mutations [16,17]

Summary

Introduction

Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are implicated in the HBC phenotype. Germline mutations of the tumor suppressor gene TP53 account for more than half of the families with classic Li-Fraumeni syndrome (LFS) [1], which is an inherited condition characterized by the development of sarcomas and other early-onset tumors, including breast cancer [2,3]. As far as we are aware, germline BRCA1 mutations have not been detected in LFS/LFL kindreds, not even among families presenting a complex cancer history consistent both with LFL and other syndromes that constitute the HBC phenotype [6,8,11,18]

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