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Nobusawa S.,International Agency for Research on Cancer IARC | Lachuer J.,ProfileXpert | Wierinckx A.,ProfileXpert | Kim Y.H.,International Agency for Research on Cancer IARC | And 6 more authors.
Brain Pathology

Glioblastomas are morphologically and genetically heterogeneous, but little is known about the regional patterns of genomic imbalance within glioblastomas. We recently established a reliable whole genome amplification (WGA) method to randomly amplify DNA from paraffin-embedded histological sections with minimum amplification bias [Huang et al (J Mol Diagn 11: 109-116, 2009)]. In this study, chromosomal imbalance was assessed by array comparative genomic hybridization (CGH; Agilent 105K, Agilent Technologies, Santa Clara, CA, USA), using WGA-DNA from two to five separate tumor areas of 14 primary glioblastomas (total, 41 tumor areas). Chromosomal imbalances significantly differed among glioblastomas; the only alterations that were observed in ≥6 cases were loss of chromosome 10q, gain at 7p and loss of 10p. Genetic alterations common to all areas analyzed within a single tumor included gains at 1q32.1 (PIK3C2B, MDM4), 4q11-q12 (KIT, PDGFRA), 7p12.1-11.2 (EGFR), 12q13.3-12q14.1 (GLI1, CDK4) and 12q15 (MDM2), and loss at 9p21.1-24.3 (p16INK4a/p14ARF), 10p15.3-q26.3 (PTEN, etc.) and 13q12.11-q34 (SPRY2, RB1). These are likely to be causative in the pathogenesis of glioblastomas (driver mutations). In addition, there were numerous tumor area-specific genomic imbalances, which may be either nonfunctional (passenger mutations) or functional, but constitute secondary events reflecting progressive genomic instability, a hallmark of glioblastomas. © 2010 World Health Organization. Source

Szathmari A.,University of Lyon | Champier J.,University of Lyon | Ghersi-Egea J.-F.,University of Lyon | Jouvet A.,University of Lyon | And 3 more authors.

Circumventricular organs (CVOs) are specialized ventricular structures around the third and fourth ventricles of the brain. In humans, these structures are present during the fetal period and some become vestigial after birth. Some of these organs, such as the pineal gland (PG), subcommissural organ (SCO), and organum vasculosum of the lamina terminalis, might be the sites of origin of periventricular tumors, notably pineal parenchymal tumors, papillary tumor of the pineal region and chordoid glioma. In contrast to the situation in humans, CVOs are present in the adult rat and can be dissected by laser capture microdissection (LCM). In this study, we used LCM and microarrays to analyze the transcriptomes of three CVOs, the SCO, the subfornical organ (SFO), and the PG and the third ventricle ependyma in the adult rat, in order to better characterize these organs at the molecular level. Several genes were expressed only, or mainly, in one of these structures, for example, Erbb2 and Col11a1 in the ependyma, Epcam and Claudin-3 (CLDN3) in the SCO, Ren1 and Slc22a3 in the SFO and Tph, Aanat and Asmt in the PG. The expression of these genes in periventricular tumors should be examined as evidence for a possible origin from the CVOs. Furthermore, we performed an immunohistochemical study of CLDN3, a membrane protein involved in forming cellular tight junctions and found that CLDN3 expression was restricted to the apical pole of ependymocytes in the SCO. This microarray study provides new evidence regarding the possible origin of some rare periventricular tumors. © 2012 Japanese Society of Neuropathology. Source

Wierinckx A.,University of Lyon | Wierinckx A.,University Claude Bernard Lyon 1 | Raverot G.,University of Lyon | Nazaret N.,ProfileXpert | And 5 more authors.
Molecular and Cellular Endocrinology

Predicting pituitary tumor behavior remains a challenge, since the prognostic value of identified pathological markers has not yet been evaluated. Genome-wide transcriptome analyses allow the identification of molecular markers to highlight global changes in gene expression and enable the discovery of signaling pathways within complex biological networks. While several transcriptome studies comparing normal with tumoral pituitary as a whole or with respect to subtype have given interesting data concerning pituitary pathogenesis, none have considered pituitary tumor prognosis. Only one study to date, focusing on the pathological classification and progression of prolactin tumors, has identified some molecular markers with diagnostic and prognostic value. We reviewed data in the literature on human pituitary tumor transcriptome and conducted a meta-analysis on the expression of genes involved in cell growth, proliferation and the cell cycle. Based on our expertise, we evaluate the interests and the limitations of using this approach with human pituitary tumors. © 2010 Elsevier Ireland Ltd. Source

Nagarajan M.,Ecole Normale Superieure de Lyon | Veyrieras J.-B.,Ecole Normale Superieure de Lyon | de Dieuleveult M.,Ecole Normale Superieure de Lyon | Bottin H.,Ecole Normale Superieure de Lyon | And 6 more authors.
PLoS Genetics

Epigenomes commonly refer to the sequence of presence/absence of specific epigenetic marks along eukaryotic chromatin. Complete histone-borne epigenomes have now been described at single-nucleosome resolution from various organisms, tissues, developmental stages, or diseases, yet their intra-species natural variation has never been investigated. We describe here that the epigenomic sequence of histone H3 acetylation at Lysine 14 (H3K14ac) differs greatly between two unrelated strains of the yeast Saccharomyces cerevisiae. Using single-nucleosome chromatin immunoprecipitation and mapping, we interrogated 58,694 nucleosomes and found that 5,442 of them differed in their level of H3K14 acetylation, at a false discovery rate (FDR) of 0.0001. These Single Nucleosome Epi-Polymorphisms (SNEPs) were enriched at regulatory sites and conserved non-coding DNA sequences. Surprisingly, higher acetylation in one strain did not imply higher expression of the relevant gene. However, SNEPs were enriched in genes of high transcriptional variability and one SNEP was associated with the strength of gene activation upon stimulation. Our observations suggest a high level of inter-individual epigenomic variation in natural populations, with essential questions on the origin of this diversity and its relevance to gene x environment interactions. © 2010 Nagarajan et al. Source

Dacheux E.,University of Lyon | Dacheux E.,French Institute of Health and Medical Research | Dacheux E.,French National Center for Scientific Research | Dacheux E.,Equipe Labellisee Ligue 2008 | And 24 more authors.

BRCA1 (Breast Cancer 1) has been implicated in a number of cellular processes, including transcription regulation, DNA damage repair and protein ubiquitination. We previously demonstrated that BRCA1 interacts with PABP1 (Poly(A)-Binding Protein 1) and that BRCA1 modulates protein synthesis through this interaction. To identify the mRNAs that are translationally regulated by BRCA1, we used a microarray analysis of polysome-bound mRNAs in BRCA1-depleted and non-depleted MCF7 cells. Our findings show that BRCA1 modifies the translational efficiency of approximately 7% of the mRNAs expressed in these cells. Further analysis revealed that several processes contributing to cell surveillance such as cell cycle arrest, cell death, cellular growth and proliferation, DNA repair and gene expression, are largely enriched for the mRNAs whose translation is impacted by BRCA1. The BRCA1-dependent translation of these species of mRNAs therefore uncovers a novel mechanism through which BRCA1 exerts its onco-suppressive role. In addition, the BRCA1-dependent translation of mRNAs participating in unexpected functions such as cellular movement, nucleic acid metabolism or protein trafficking is indicative of novel functions for BRCA1. Finally, this study contributes to the identification of several markers associated with BRCA1 deficiency and to the discovery of new potential anti-neoplastic therapeutic targets. © 2013 Dacheux et al. Source

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