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Background: Molecular segmentation of breast cancer allows identification of small groups of patients who present high sensitivity to targeted agents. A patient, with chemo- and trastuzumab-resistant HER2-overexpressing breast cancer, who presented concomitant acute promyelocytic leukemia, showed a response in her breast lesions to retinoic acid, arsenic, and aracytin. We therefore investigated whether RARA gene amplification could be associated with sensitivity to retinoic acid derivatives in breast cancers., Materials and Methods: Array comparative genomic hybridization and gene expression arrays were used to characterize RARA amplifications and expression in 103 breast cancer samples. In vitro activity of ATRA was characterized in T47D, SKBR3, and BT474 cell lines., Results: Retinoic acid receptor alpha was gained or amplified in 27% of HER2-positive and 13% of HER2-negative breast cancer samples. Retinoic acid receptor alpha can be coamplified with HER2. Retinoic acid receptor alpha copy number changes could be correlated with messenger RNA expression. All-trans-retinoic acid reduced cell viability of RARA-amplified, but not RARA-normal, cell lines through apoptosis. Gene expression arrays showed that ATRA-induced apoptosis in RARA-amplified cell lines was related to an increase in CASP1 and IRF1., Conclusion: The results of this study suggest that breast cancers exhibiting RARA amplifications could be sensitive to retinoic acid. A phase II trial will evaluate this hypothesis in the clinical setting., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Recently, the gene encoding the human cytosolic NADPH-dependent isocitrate dehydrogenase (IDH1) was reported frequently mutated in gliomas. Rare mutations were also found in the sequence of the mitochondrial isoform IDH2., Methods: In a series of 764 gliomas genome-wide characterized, we determined the presence of mutations in the sequences of both IDH1 and IDH2 genes by direct sequencing., Results: We found that all tumors with complete 1p19q codeletion (n = 128) were mutated in the IDH1 (118) or IDH2 (10) gene. This 100% mutation rate contrasted strikingly with other gliomas exhibiting either variable 1p and 19q alterations (n = 159, IDH1/IDH2 mutation rate of 33%) or no 1p19q alteration (n = 477, IDH1/IDH2 mutation rate 32%). Our data also confirm the prognostic impact of IDH1/IDH2 mutation in gliomas whatever grade considered: patients harboring mutations of IDH1/IDH2 have an improved median overall survival. Moreover, in WHO grade II and III gliomas, 3 groups with significantly different outcomes were identified according to their 1p19q and IDH1/IDH2 statuses. Tumors carrying both alterations had longer overall survival than their nonmutated counterpart., Conclusions: This exclusive association suggests a new mechanism of tumorigenesis. Perhaps the IDH1/IDH2 mutation is a prerequisite for the occurrence of the t(1;19) translocation, or it is required for the 1p19q codeleted cells to acquire a tumor phenotype.