Large genomic deletions inactivate the BRCA2 gene in breast cancer families

• Published in: Journal of medical genetics Vol. 42; no. 10; p. e64
• Main Authors: Agata, S, Dalla Palma, M, Callegaro, M, Scaini, M C, Menin, C, Ghiotto, C, Nicoletto, O, Zavagno, G, Chieco-Bianchi, L, D’Andrea, E, Montagna, M
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.10.2005; BMJ Publishing Group LTD; BMJ Group
• Subjects: BRCA2; BRCA2 Protein - genetics; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cloning, Molecular; denaturing high performance liquid chromatography; DHPLC; DNA Mutational Analysis; Exons; Female; Gene Deletion; Genes; Genetic Predisposition to Disease; Genetic Testing - methods; Genome; genomic rearrangement; HBC/HBOC; hereditary breast cancer; hereditary breast/ovarian cancer; Humans; MLPA; Models, Genetic; Molecular Sequence Data; multiplex ligation dependent probe amplification; Mutation; Online Mutation Report; Recombination, Genetic; SHBC/SHBOC; Studies; suspected hereditary breast/ovarian cancer; California
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2005.032789

Background:BRCA1 and BRCA2 are the two major genes responsible for the breast and ovarian cancers that cluster in families with a genetically determined predisposition. However, regardless of the mutation detection method employed, the percentage of families without identifiable alterations of these genes exceeds 50%, even when applying stringent criteria for family selection. A small but significant increase in mutation detection rate has resulted from the discovery of large genomic alterations in BRCA1. A few studies have addressed the question of whether BRCA2 might be inactivated by the same kinds of alteration, but most were either done on a relatively small number of samples or employed cumbersome mutation detection methods of variable sensitivity. Objective: To analyse 121 highly selected families using the recently available BRCA2 multiplex ligation dependent probe amplification (MLPA) technique. Results: Three different large genomic deletions were identified and confirmed by analysis of the mutant transcript and genomic characterisation of the breakpoints. Conclusions: Contrary to initial suggestions, the presence of BRCA2 genomic rearrangements is worth investigating in high risk breast or ovarian cancer families.