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Accueil Nota Bene Cancer V2 Numéro 90 du 17 May 2011 Biologie

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Nota Bene Cancer Numéro 90 du 17 May 2011 RSS

Biologie

Aberrations chromosomiques

Menée sur 149 échantillons tumoraux issus du Cancer Genome Atlas, cette étude identifie, à partir d'une analyse de corrélation entre les mutations somatiques et l'expression de gènes, un ensemble de gènes jouant un rôle important dans la progression d'un glioblastome

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    Menée sur 149 échantillons tumoraux issus du Cancer Genome Atlas, cette étude identifie, à partir d'une analyse de corrélation entre les mutations somatiques et l'expression de gènes, un ensemble de gènes jouant un rôle important dans la progression d'un glioblastome

    “Correlation of Somatic Mutation and Expression Identifies Genes Important in Human Glioblastoma Progression and Survival”

    • Masica, David L.;Karchin, Rachel

    Cooperative dysregulation of gene sequence and expression may contribute to cancer formation and progression. The Cancer Genome Atlas (TCGA) Network recently catalogued gene sequence and expression data for a collection of glioblastoma multiforme (GBM) tumors. We developed an automated, model-free method to rapidly and exhaustively examine the correlation among somatic mutation and gene expression and interrogated 149 GBM tumor samples from the TCGA. The method identified 41 genes whose mutation status is highly correlated with drastic changes in the expression (z-score ± 2.0), across tumor samples, of other genes. Some of the 41 genes have been previously implicated in GBM pathogenesis (e.g., NF1, TP53, RB1, and IDH1) and others, while implicated in cancer, had not previously been highlighted in studies using TCGA data (e.g., SYNE1, KLF6, FGFR4, and EPHB4). The method also predicted that known oncogenes and tumor suppressors participate in GBM via drastic over- and underexpression, ...


Mots clés : Système nerveux central; Biologie (Aberrations chromosomiques)

A partir de l'analyse d'échantillons prélevés sur 42 patients atteints d'une leucémie myélomonocytaire chronique, cette étude suggère que la voie de signalisation Notch peut jouer un rôle de suppresseur ou de promoteur de tumeurs au sein d'un même tissu

  • A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia
    Nature, Vol. 473 (7346), pp. 230-233, 2011 (résumé)
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    A partir de l'analyse d'échantillons prélevés sur 42 patients atteints d'une leucémie myélomonocytaire chronique, cette étude suggère que la voie de signalisation Notch peut jouer un rôle de suppresseur ou de promoteur de tumeurs au sein d'un même tissu

    “A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia”

    • Klinakis, Apostolos;Lobry, Camille;Abdel-Wahab, Omar;Oh, Philmo;Haeno, Hiroshi;Buonamici, Silvia;van De Walle, Inge;Cathelin, Severine;Trimarchi, Thomas;Araldi, Elisa;Liu, Cynthia;Ibrahim, Sherif;Beran, Miroslav;Zavadil, Jiri;Efstratiadis, Argiris;Taghon, Tom;Michor, Franziska;Levine, Ross L.;Aifantis, Iannis

    Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types1. Its activity is controlled by the multi-subunit γ-secretase (γSE) complex2. Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations3. Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target ...


  • Cancer: The flipside of Notch
    Nature, Vol. 473 (7346), pp. 159-160, 2011 (commentaire)
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    A partir de l'analyse d'échantillons prélevés sur 42 patients atteints d'une leucémie myélomonocytaire chronique, cette étude suggère que la voie de signalisation Notch peut jouer un rôle de suppresseur ou de promoteur de tumeurs au sein d'un même tissu

    “Cancer: The flipside of Notch”

    • Kalaitzidis, Demetrios ; Armstrong, Scott A.


Mots clés : Leucémie; Biologie (Aberrations chromosomiques)

Menée sur 20 échantillons de tumeurs de la prostate et 10 échantillons de tissus sains, cette étude de séquençage du transcriptome identifie la présence préférentielle d'ARNs chimériques dans les tumeurs

  • Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing
    Proceedings of the National Academy of Sciences, Vol. 108 (22), pp. 9172-9177, 2011 (rapport technique en libre accès)
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    Menée sur 20 échantillons de tumeurs de la prostate et 10 échantillons de tissus sains, cette étude de séquençage du transcriptome identifie la présence préférentielle d'ARNs chimériques dans les tumeurs

    “Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing”

    • Kannan, Kalpana;Wang, Liguo;Wang, Jianghua;Ittmann, Michael M.;Li, Wei;Yen, Laising

    Transcription-induced chimeric RNAs, possessing sequences from different genes, are expected to increase the proteomic diversity through chimeric proteins or altered regulation. Despite their importance, few studies have focused on chimeric RNAs especially regarding their presence/roles in human cancers. By deep sequencing the transcriptome of 20 human prostate cancer and 10 matched benign prostate tissues, we obtained 1.3 billion sequence reads, which led to the identification of 2,369 chimeric RNA candidates. Chimeric RNAs occurred in significantly higher frequency in cancer than in matched benign samples. Experimental investigation of a selected 46 set led to the confirmation of 32 chimeric RNAs, of which 27 were highly recurrent and previously undescribed in prostate cancer. Importantly, a subset of these chimeras was present in prostate cancer cell lines, but not detectable in primary human prostate epithelium cells, implying their associations with cancer. These chimeras contain ...


Mots clés : Prostate; Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée in vitro et sur un modèle murin de cancer de la prostate, cette étude identifie un mécanisme par lequel COP1, le gène d'une ubiquitine-ligase, joue un rôle de suppresseur de tumeurs

  • COP1 is a tumour suppressor that causes degradation of ETS transcription factors
    Nature, Vol. 474 (7351), pp. 403-406, 2011 (résumé)
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    Menée in vitro et sur un modèle murin de cancer de la prostate, cette étude identifie un mécanisme par lequel COP1, le gène d'une ubiquitine-ligase, joue un rôle de suppresseur de tumeurs

    “COP1 is a tumour suppressor that causes degradation of ETS transcription factors”

    • Vitari, Alberto C.;Leong, Kevin G.;Newton, Kim;Yee, Cindy;O/'Rourke, Karen;Liu, Jinfeng;Phu, Lilian;Vij, Rajesh;Ferrando, Ronald;Couto, Suzana S.;Mohan, Sankar;Pandita, Ajay;Hongo, Jo-Anne;Arnott, David;Wertz, Ingrid E.;Gao, Wei-Qiang;French, Dorothy M.;Dixit, Vishva M.

    The proto-oncogenes ETV1, ETV4 and ETV5 encode transcription factors in the E26 transformation-specific (ETS) family, which includes the most frequently rearranged and overexpressed genes in prostate cancer1, 2, 3, 4. Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COP1 (also known as RFWD2) as a tumour suppressor that negatively regulates ETV1, ETV4 and ETV5. ETV1, which is mutated in prostate cancer more often, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs and was 50-fold more stable than wild-type ETV1. Almost all patient translocations render ETV1 insensitive to COP1, implying that this confers a selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 and produced increased cell proliferation, hyperplasia, and early prostate ...


Mots clés : Prostate; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur des lignées cellulaires, cette étude identifie un mécanisme par lequel BRCA2 joue un rôle de suppresseur de tumeurs en maintenant l'intégrité génomique

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    Menée sur des lignées cellulaires, cette étude identifie un mécanisme par lequel BRCA2 joue un rôle de suppresseur de tumeurs en maintenant l'intégrité génomique

    “Double-Strand Break Repair-Independent Role for BRCA2 in Blocking Stalled Replication Fork Degradation by MRE11”

    • Schlacher, Katharina;Christ, Nicole;Siaud, Nicolas;Egashira, Akinori;Wu, Hong;Jasin, Maria

    Breast cancer suppressor BRCA2 is critical for maintenance of genomic integrity and resistance to agents that damage DNA or collapse replication forks, presumably through homology-directed repair of double-strand breaks (HDR). Using single-molecule DNA fiber analysis, we show here that nascent replication tracts created before fork stalling with hydroxyurea are degraded in the absence of BRCA2 but are stable in wild-type cells. BRCA2 mutational analysis reveals that a conserved C-terminal site involved in stabilizing RAD51 filaments, but not in loading RAD51 onto DNA, is essential for this fork protection but dispensable for HDR. RAD51 filament disruption in wild-type cells phenocopies BRCA2 deficiency. BRCA2 prevents chromosomal aberrations on replication stalling, which are alleviated by inhibition of MRE11, the nuclease responsible for this form of fork instability. Thus, BRCA2 prevents rather than repairs nucleolytic lesions at stalled replication forks to maintain genomic ...


Mots clés : Sein; Biologie (Oncogènes et suppresseurs de tumeurs)

Cet article passe en revue les travaux récents sur les cellules souches cancéreuses et le micro-environnement tumoral dans les cancers du système nerveux

  • Deadly Teamwork: Neural Cancer Stem Cells and the Tumor Microenvironment
    Cell stem cell, Vol. 8 (5), pp. 482-485, 2011 (résumé)
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    Cet article passe en revue les travaux récents sur les cellules souches cancéreuses et le micro-environnement tumoral dans les cancers du système nerveux

    “Deadly Teamwork: Neural Cancer Stem Cells and the Tumor Microenvironment”

    • Lathia, Justin D;Heddleston, John M;Venere, Monica;Rich, Jeremy N

    Neural cancers display cellular hierarchies with self-renewing tumorigenic cancer stem cells (CSCs) at the apex. Instructive cues to maintain CSCs are generated by both intrinsic networks and the niche microenvironment. The CSC-microenvironment relationship is complex, as CSCs can modify their environment and extrinsic forces induce plasticity in the cellular hierarchy.


Mots clés : Système nerveux central; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée in vitro et in vivo, cette étude montre que, des deux kinases B-Raf et C-Raf, seule la seconde est nécessaire pour la formation d'une tumeur du poumon présentant une mutation K-RASG12D

  • C-Raf Is Required for the Initiation of Lung Cancer by K-RasG12D
    Cancer Discovery, Vol. 1 (2), pp. 128-136, 2011 (rapport technique en libre accès)
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    Menée in vitro et in vivo, cette étude montre que, des deux kinases B-Raf et C-Raf, seule la seconde est nécessaire pour la formation d'une tumeur du poumon présentant une mutation K-RASG12D

    “C-Raf Is Required for the Initiation of Lung Cancer by K-RasG12D”

    • Karreth, Florian A.;Frese, Kristopher K.;DeNicola, Gina M.;Baccarini, Manuela;Tuveson, David A.

    The Ras/Raf/MEK/ERK (extracellular signal–regulated kinase) pathway is primarily responsible for mitogenesis in metazoans, and mutational activation of this pathway is common in cancer. A variety of selective chemical inhibitors directed against the mitogen-activated protein kinase pathway are now available for clinical investigation and thus the determination of the importance of each of the kinases in oncogenesis is paramount. We investigated the role of two Raf kinases, B-Raf and C-Raf, in Ras oncogenesis, and found that although B-Raf and C-Raf have overlapping functions in primary mesenchymal cells, C-Raf but not B-Raf is required for the proliferative effects of K-RasG12D in primary epithelial cells. Furthermore, in a lung cancer mouse model, C-Raf is essential for tumor initiation by oncogenic K-RasG12D, whereas B-Raf is dispensable for this process. Our findings reveal that K-RasG12D elicits its oncogenic effects primarily through C-Raf and suggest that selective C-Raf ...


Mots clés : Poumon; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide de modèles murins, cette étude montre que des programmes différents de transcription de p53 sont activés dans la réponse aux atteintes à l'ADN et dans la suppression des tumeurs

  • Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
    Cell, Vol. 145 (4), pp. 571-583, 2011 (rapport technique en libre accès)
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    Menée à l'aide de modèles murins, cette étude montre que des programmes différents de transcription de p53 sont activés dans la réponse aux atteintes à l'ADN et dans la suppression des tumeurs

    “Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression”

    • Brady, Colleen A;Jiang, Dadi;Mello, Stephano S;Johnson, Thomas M;Jarvis, Lesley A;Kozak, Margaret M;Broz, Daniela Kenzelmann;Basak, Shashwati;Park, Eunice J;McLaughlin, Margaret E;Karnezis, Anthony N;Attardi, Laura D

    The molecular basis for p53-mediated tumor suppression remains unclear. Here, to elucidate mechanisms of p53 tumor suppression, we use knockin mice expressing an allelic series of p53 transcriptional activation mutants. Microarray analysis reveals that one mutant, p5325,26, is severely compromised for transactivation of most p53 target genes, and, moreover, p5325,26 cannot induce G1-arrest or apoptosis in response to acute DNA damage. Surprisingly, p5325,26 retains robust activity in senescence and tumor suppression, indicating that efficient transactivation of the majority of known p53 targets is dispensable for these pathways. In contrast, the transactivation-dead p5325,26,53,54 mutant cannot induce senescence or inhibit tumorigenesis, like p53 nullizygosity. Thus, p53 transactivation is essential for tumor suppression but, intriguingly, in association with a small set of novel p53 target genes. Together, our studies distinguish the p53 transcriptional programs involved in acute ...


Mots clés : Cancer (général); Biologie (Oncogènes et suppresseurs de tumeurs)

Progression et métastases

Cette étude montre la faisabilité d'une nouvelle méthode pour caractériser des métastases osseuses de patients décédés d'un cancer de la prostate

  • Characterization of Bone Metastases from Rapid Autopsies of Prostate Cancer Patients
    Clinical Cancer Research, Vol. 17 (12), pp. 3924-3932, 2011 (rapport technique en libre accès)
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    Cette étude montre la faisabilité d'une nouvelle méthode pour caractériser des métastases osseuses de patients décédés d'un cancer de la prostate

    “Characterization of Bone Metastases from Rapid Autopsies of Prostate Cancer Patients”

    • Mehra, Rohit;Kumar-Sinha, Chandan;Shankar, Sunita;Lonigro, Robert J.;Jing, Xiaojun;Philips, Neena E.;Siddiqui, Javed;Han, Bo;Cao, Xuhong;Smith, David C.;Shah, Rajal B.;Chinnaiyan, Arul M.;Pienta, Kenneth J.

    Purpose: Bone is the most common metastatic site for prostate cancer, and osseous metastases are the leading cause of morbidity from this disease. Recent autopsy studies prove that 100% of men who die of prostate cancer have bone involvement. Understanding the biology of prostate cancer and its evolution to an incurable androgen-independent phenotype requires an understanding of the genetic and cellular alterations that lead to the seeding and proliferation of tumor foci in bone, as well as the microenvironment in which these metastases arise. No intensive studies, however, have been conducted on osseous metastatic tissues from patients with metastatic prostate cancer due to lack of access to such tissues for profiling and other research.Experimental Design: We show, for the first time, a reproducible methodology to obtain high quality clinical tumor tissues metastatic to the bone. This technique allowed the procurement of viable metastatic tumor tissue from involved bones in 13 ...


Mots clés : Os; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur le rôle des neurotransmetteurs dans la progression tumorale

  • The neuronal influence on tumor progression
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Vol. 1816 (2), pp. 105-118, 2011 (résumé)
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    Cet article passe en revue les travaux récents sur le rôle des neurotransmetteurs dans la progression tumorale

    “The neuronal influence on tumor progression”

    • Mancino, Mario;Ametller, Elisabet;Gascón, Pedro;Almendro, Vanessa

    Nerve fibers accompany blood and lymphatic vessels all over the body. An extensive amount of knowledge has been obtained with regard to tumor angiogenesis and tumor lymphangiogenesis, yet little is known about the potential biological effects of "neoneurogenesis". Cancer cells can exploit the advantage of the factors released by the nerve fibers to generate a positive microenvironment for cell survival and proliferation. At the same time, they can stimulate the formation of neurites by secreting neurotrophic factors and axon guidance molecules. The neuronal influence on the biology of a neoplasm was initially described several decades ago. Since then, an increasing amount of experimental evidence strongly suggests the existence of reciprocal interactions between cancer cells and nerves in humans. Moreover, researchers have been able to demonstrate a crosstalk between cancer cells and nerve fibers as a strategy for survival. Despite all these evidence, a lot remains to be done in order ...


Mots clés : Cancer (général); Biologie (Progression et métastases)

Ressources et infrastructures (Biologie)

Cet article décrit la tumorothèque d'un des principaux groupes coopérateurs du National Cancer Institute américain (SWOG) et présente les modes d'accès à ces ressources pour les chercheurs

  • SWOG Cooperative Group Biorepository Resource: Access for Scientific Research Studies
    Clinical Cancer Research, Vol. 17 (16), pp. 5239-5246, 2011 (résumé)
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    Cet article décrit la tumorothèque d'un des principaux groupes coopérateurs du National Cancer Institute américain (SWOG) et présente les modes d'accès à ces ressources pour les chercheurs

    “SWOG Cooperative Group Biorepository Resource: Access for Scientific Research Studies”

    • Hoban, Carolyn J.;Franklin, Wilbur;Kopecky, Kenneth J.;Baker, Laurence H.

    SWOG (formerly the Southwest Oncology Group), a National Cancer Institute–supported cooperative group, conducts multiinstitutional, multidisciplinary clinical trials for adult patients with cancer, covering a wide range of solid tumors and hematologic cancers. The group has amassed a large set of biospecimens, collected from patients in numerous studies over many years and linked to clinical data. SWOG is now actively promoting the use of this unique scientific resource by making it available to a much wider group of researchers. This biospecimen resource offers material for research on disease mechanisms, genomic changes associated with cancer progression, markers of response and resistance to therapies, diagnosis or detection of recurrence, and more. By collecting, storing, and distributing the specimens, SWOG provides the framework for translational scientists to complete the feedback loop from “bedside to bench.” This article provides an overview of the group's biospecimen ...


Mots clés : Cancer (général); Biologie (Ressources et infrastructures (Biologie))

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