title: Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.
abstract: BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.
authors.affiliation: Centre de Recherche, University Paris-Descartes, Paris, France.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Popova
authors.forename: Elodie
authors.initials: E
authors.lastname: Manié
authors.forename: Guillaume
authors.initials: G
authors.lastname: Rieunier
authors.forename: Virginie
authors.initials: V
authors.lastname: Caux-Moncoutier
authors.forename: Carole
authors.initials: C
authors.lastname: Tirapo
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sigal-Zafrani
authors.forename: Marc
authors.initials: M
authors.lastname: Bollet
authors.forename: Michel
authors.initials: M
authors.lastname: Longy
authors.forename: Claude
authors.initials: C
authors.lastname: Houdayer
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre-Garau
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Marc-Henri
authors.initials: MH
authors.lastname: Stern
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005820:Genetic Testing / Q000379:methods*; D042822:Genomic Instability; D006801:Humans; D011003:Ploidies; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012680:Sensitivity and Specificity