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Le Touquet – Paris-Plage, France

Rouault A.,French Institute of Health and Medical Research | Banneau G.,French Institute of Health and Medical Research | MacGrogan G.,French Institute of Health and Medical Research | MacGrogan G.,Bergonie Cancer Institute | And 14 more authors.
PLoS ONE | Year: 2012

Introduction: Germline 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. Methods: To 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. Results: We 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. Conclusion: Together 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. © 2012 Rouault et al. Source

Brambilla C.,Institut Universitaire de France | Brambilla C.,Joseph Fourier University | Laffaire J.,Cartes dIdentite des Tumeurs CIT Program | Lantuejoul S.,Institut Universitaire de France | And 10 more authors.
Clinical Cancer Research | Year: 2014

Purpose: The basaloid carcinoma (pure) and the (mixed) basaloid variant of lung squamous cell carcinoma (SCC) have a dismal prognosis but their underlying specific molecular characteristics remain obscure and no therapy has proven to be efficient. Experimental Design: To assess their molecular specificity among other lung SCCs we analyzed DNA copy number aberrations and mRNA expression pangenomic profiles of 93 SCCs, including 42 basaloid samples (24 pure, 18 mixed). Results: Supervised analyses reveal that pure basaloid tumors display a specificmRNAexpression profile, encoding factors controlling the cell cycle, transcription, chromatin, and splicing, with prevalent expression in germline and stem cells, while genes related to squamous differentiation are underexpressed. From this signature, we derived a 2-genes (SOX4, IVL) immunohistochemistry-based predictor that discriminated basaloid tumors (pure and mixed) from non-basaloid tumors with 94% accuracy in an independent series. The pure basaloid tumors are also distinguished through unsupervised analyses. Using a centroid-based predictor, the corresponding molecular subtype was found in 8 independent public datasets (n = 58/533), and was shown to be associated with a very poor survival as compared with other SCCs (adjustedHR = 2.45; P = 0.000001). Conclusion: This study enlightens the heterogeneity of SCCs that can be subclassified in mRNA expression subtypes. This study demonstrates for the first time that basaloid SCCs constitute a distinct histomolecular entity, which justifies its recognition and distinction from non-basaloid SCCs. In addition, their characteristic molecular profile highlights their intrinsic resistance to cytotoxic chemotherapy and could serve as a guide for targeted therapies. ©2014 AACR. Source

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