Cet article passe en revue les travaux récents sur des mécanismes de cancérogenèse associés à des mutations de gènes codant pour des régulateurs épigénétiques

Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer

Plass, Christoph ; Pfister, Stefan M. ; Lindroth, Anders M. ; Bogatyrova, Olga ; Claus, Rainer ; Lichter, Peter

Malignancies are characterized by extensive global reprogramming of epigenetic patterns, including gains or losses in DNA methylation and changes to histone marks. Furthermore, high-resolution genome-sequencing efforts have discovered a wealth of mutations in genes encoding epigenetic regulators that have roles as 'writers', 'readers' or 'editors' of DNA methylation and/or chromatin states. In this Review, we discuss how these mutations have the potential to deregulate hundreds of targeted [...]

Menée in vitro à l'aide d'une méthode à haut débit appelée MAPit-patch, cette étude met en évidence une hétérogénéité épigénétique des populations de cellules tumorales de glioblastomes

Multiplex mapping of chromatin accessibility and DNA methylation within targeted single molecules identifies epigenetic heterogeneity in neural stem cells and glioblastoma

Nabilsi, Nancy H. ; Deleyrolle, Loic P. ; Darst, Russell P. ; Riva, Alberto ; Reynolds, Brent A. ; Kladde, Michael P.

Human tumors are comprised of heterogeneous cell populations that display diverse molecular and phenotypic features. To examine the extent to which epigenetic differences contribute to intratumoral cellular heterogeneity, we have developed a high-throughput method, termed MAPit-patch. The method uses multiplexed amplification of targeted sequences from sub-microgram quantities of genomic DNA followed by next generation bisulfite sequencing. This provides highly scalable and simultaneous mapping [...]

Menée sur des échantillons de tumeurs primitives et de métastases prélévés sur des patients atteints d'un neuroblastome, cette étude identifie des anomalies génomiques associées au risque de métastase

Recurrent pre-existing and acquired DNA copy number alterations, including focal TERT gains, in neuroblastoma central nervous system metastases

Cobrinik, David ; Ostrovnaya, Irina ; Hassimi, Maryam ; Tickoo, Satish K. ; Cheung, Irene Y. ; Cheung, Nai-Kong V.

Stage 4 neuroblastomas have a high rate of local and metastatic relapse and associated disease mortality. The central nervous system (CNS) is currently one of the most common isolated relapse sites, yet the genomic alterations that contribute to these metastases are unknown. This study sought to identify recurrent DNA copy number alterations (CNAs) and target genes relating to neuroblastoma CNS metastases by studying 19 pre-CNS primary tumors and 27 CNS metastases, including 12 matched pairs. [...]

Menée dans le cadre du projet "The Cancer Genome Atlas" portant sur plus de 500 échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, cette étude décrit le paysage des altérations génomiques somatiques en association avec des caractéristiques cliniques

The Somatic Genomic Landscape of Glioblastoma

Brennan, Cameron W ; Verhaak, Roel G W. ; McKenna, Aaron ; Campos, Benito ; Noushmehr, Houtan ; Salama, Sofie R ; Zheng, Siyuan ; Chakravarty, Debyani ; Sanborn, J.  Zachary ; Berman, Samuel H ; Beroukhim, Rameen ; Bernard, Brady ; Wu, Chang-Jiun ; Genovese, Giannicola ; Shmulevich, Ilya ; Barnholtz-Sloan, Jill ; Zou, Lihua ; Vegesna, Rahulsimham ; Shukla, Sachet A ; Ciriello, Giovanni ; Yung, W. K. ; Zhang, Wei ; Sougnez, Carrie ; Mikkelsen, Tom ; Aldape, Kenneth ; Bigner, Darell D ; Van Meir, Erwin G ; Prados, Michael ; Sloan, Andrew ; Black, Keith L ; Eschbacher, Jennifer ; Finocchiaro, Gaetano ; Friedman, William ; Andrews, David W ; Guha, Abhijit ; Iacocca, Mary ; O Neill, Brian P ; Foltz, Greg ; Myers, Jerome ; Weisenberger, Daniel J ; Penny, Robert ; Kucherlapati, Raju ; Perou, Charles M ; Hayes, D.  Neil ; Gibbs, Richard ; Marra, Marco ; Mills, Gordon B ; Lander, Eric ; Spellman, Paul ; Wilson, Richard ; Sander, Chris ; Weinstein, John ; Meyerson, Matthew ; Gabriel, Stacey ; Laird, Peter W ; Haussler, David ; Getz, Gad ; Chin, Lynda

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is [...]

Menée sur 327 échantillons tumoraux prélevés sur des patients atteints d'un carcinome urothélial de la vessie, cette étude identifie un polymorphisme à simple nucléotide associé aux effets exercés par des mutations du gène TERT sur la récidive de la maladie

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Rachakonda, P. Sivaramakrishna ; Hosen, Ismail ; de Verdier, Petra J. ; Fallah, Mahdi ; Heidenreich, Barbara ; Ryk, Charlotta ; Wiklund, N. Peter ; Steineck, Gunnar ; Schadendorf, Dirk ; Hemminki, Kari ; Kumar, Rajiv

The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en régulant l'assemblage des télomères, l'enzyme RTEL1 joue un rôle de suppresseur de tumeurs

RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication

Vannier, Jean-Baptiste ; Sandhu, Sumit ; Petalcorin, Mark IR. ; Wu, Xiaoli ; Nabi, Zinnatun ; Ding, Hao ; Boulton, Simon J.

Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased [...]

Menée à l'aide d'un modèle murin transgénique de leucémie lymphoblastique aiguë T, cette étude met en évidence des mécanismes suggérant que la surexpression de l'oncogène MYC ne suffit pas, à elle seule, pour déclencher la cascade d'événements conduisant à la transformation maligne

MYC fails to efficiently shape malignant transformation in T-cell acute lymphoblastic leukemia

Loosveld, Marie ; Bonnet, Mélanie ; Gon, Stéphanie ; Montpellier, Bertrand ; Quilichini, Benoit ; Navarro, Jean-Marc ; Crouzet, Thomas ; Goujart, Marie-Amélie ; Chasson, Lionel ; Morgado, Ester ; Picard, Christophe ; Hernandez, Lucie ; Fossat, Chantal ; Gabert, Jean ; Michel, Gérard ; Nadel, Bertrand ; Payet-Bornet, Dominique

MYC is a potent oncogene involved in ∼70% of human cancers, inducing tumorigenesis with high penetrance and short latency in experimental transgenic models. Accordingly, MYC is recognized as a major driver of T-cell acute lymphoblastic leukemia (T-ALL) in human and zebrafish/mouse models, and uncovering the context by which MYC-mediated malignant transformation initiates and develops remains a considerable challenge. Because MYC is a very complex oncogene, highly dependent on the [...]

Menée sur des échantillons de tumeurs bénignes et malignes du sein, puis in vitro, cette étude met en évidence une dérégulation fréquente de l'expression de divers micro-ARNs associés au cancer dans les tumeurs bénignes

Deregulation of cancer-related miRNAs is a common event in both benign and malignant human breast tumors

Tahiri, Andliena ; Leivonen, Suvi-Katri ; Lüders, Torben ; Steinfeld, Israel ; Ragle Aure, Miriam ; Geisler, Jurgen ; Mäkelä, Rami ; Nord, Silje ; Riis, Margit L. H. ; Yakhini, Zohar ; Kleivi Sahlberg, Kristine ; Borresen-Dale, Anne-Lise ; Perälä, Merja ; Bukholm, Ida R.K. ; Kristensen, Vessela N.

MicroRNAs (miRNAs) are endogenous non-coding RNAs, which play an essential role in the regulation of gene expression during carcinogenesis. The role of miRNAs in breast cancer has been thoroughly investigated, and although many miRNAs are identified as cancer-related, little is known about their involvement in benign tumors. In this study, we investigated miRNA expression profiles in the two most common types of human benign tumors (fibroadenoma/ fibroadenomatosis) and in malignant breast [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels l'absence d'expression de PKM2 favorise la croissance d'une tumeur mammaire associée à la perte de BRCA1

PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells

Israelsen, William J ; Dayton, Talya L ; Davidson, Shawn M ; Fiske, Brian P ; Hosios, Aaron M ; Bellinger, Gary ; Li, Jie ; Yu, Yimin ; Sasaki, Mika ; Horner, James W ; Burga, Laura N ; Xie, Jianxin ; Jurczak, Michael J ; DePinho, Ronald A ; Clish, Clary B ; Jacks, Tyler ; Kibbey, Richard G ; Wulf, Gerburg M ; Di Vizio, Dolores ; Mills, Gordon B ; Cantley, Lewis C ; Vander Heiden, Matthew G

The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la surexpression du gène codant pour le canal ionique CLIC1 favorise le développement d'un glioblastome

Functional Role of CLIC1 Ion Channel in Glioblastoma-Derived Stem/Progenitor Cells

Setti, Matteo ; Savalli, Nicoletta ; Osti, Daniela ; Richichi, Cristina ; Angelini, Marina ; Brescia, Paola ; Fornasari, Lorenzo ; Carro, Maria Stella ; Mazzanti, Michele ; Pelicci, Giuliana

Background Chloride channels are physiologically involved in cell division and motility. Chloride intracellular channel 1 (CLIC1) is overexpressed in a variety of human solid tumors compared with normal tissues, suggesting a potential involvement of CLIC1 in the regulation of tumorigenesis. This led us to investigate the role of CLIC1 in gliomagenesis. Methods We used the neurosphere system to isolate stem/progenitor cells from human glioblastomas (GBMs). CLIC1 targeting in GBM neurospheres was [...]

Menée sur des lignées cellulaires et 100 échantillons tumoraux prélevés sur des patients atteints d'un cancer de la tête et du cou, cette étude met en évidence des mécanismes par lesquels le récepteur de la galanine GALR2 joue un rôle de suppresseur de tumeurs

Tumor suppressor activity and inactivation of galanin receptor type 2 by aberrant promoter methylation in head and neck cancer

Misawa, Yuki ; Misawa, Kiyoshi ; Kanazawa, Takeharu ; Uehara, Takayuki ; Endo, Shori ; Mochizuki, Daiki ; Yamatodani, Takashi ; Carey, Thomas E. ; Mineta, Hiroyuki

BACKGROUND There is accumulating evidence that galanin receptors (GALRs) may be tumor suppressors in head and neck squamous cell carcinoma (HNSCC). Promoter methylation status and gene expression were assessed in a large panel of head and neck primary tumors, based on the hypothesis that cytosine-guanine dinucleotide (CpG) hypermethylation might silence the galanin receptor 2 (GALR2) gene. METHODS GALR2 expression was examined in a panel of cell lines by using quantitative reverse transcription [...]

Menée sur des échantillons de muqueuse gastrique normale et de tissu tumoral, cette étude met en évidence des mécanismes par lesquels, en activant la signalisation ERK sur l'appareil de Golgi, la synbindine contribue à l'agressivité d'un cancer de l'estomac

Synbindin in Extracellular Signal-Regulated Protein Kinase Spatial Regulation and Gastric Cancer Aggressiveness

Kong, Xuan ; Qian, Jin ; Chen, Li-Sha ; Wang, Ying-Chao ; Wang, Ji-Lin ; Chen, Haoyan ; Weng, Yu-Rong ; Zhao, Shu-Liang ; Hong, Jie ; Chen, Ying-Xuan ; Zou, Weiping ; Xu, Jie ; Fang, Jing-Yuan

Background The molecular mechanisms that control the aggressiveness of gastric cancer (GC) remain poorly defined. Here we show that synbindin contributes to the aggressiveness of GC by activating extracellular signal-regulated protein kinase (ERK) signaling on the Golgi apparatus. Methods Expression of synbindin was examined in normal gastric mucosa (n = 44), intestinal metaplastic gastric mucosa (n = 66), and GC tissues (n=52), and the biological effects of synbindin on tumor growth and ERK [...]

Cet article propose un modèle du processus métastatique à partir du concept de diaspora emprunté aux sciences sociales

The Cancer Diaspora: Metastasis beyond the seed and soil hypothesis

Pienta, Kenneth J. ; Robertson, Bruce ; Coffey, Donald ; Taichman, Russell S.

Do cancer cells escape their confinement of their original habitat in the primary tumor or are they forced out by ecological changes in their home niche? Describing metastasis in terms of a simple one-way migration of cells from the primary to target organs is an insufficient concept to cover the nuances of cancer spread. A diaspora is the scattering of people away from an established homeland. To date, "diaspora" has been a uniquely human term utilized by social scientists, however, the [...]

Cet article passe en revue les travaux récents sur le rôle des vésicules membranaires dans les processus invasif et métastatique

A central role for vesicle trafficking in epithelial neoplasia: intracellular highways to carcinogenesis

Goldenring, James R.

Epithelial cell carcinogenesis involves the loss of cell polarity, alteration of polarized protein presentation, dynamic cell morphology changes, increased proliferation, and increased cell motility and invasion. Membrane vesicle trafficking underlies all of these processes. Specific membrane trafficking regulators, including RAB small GTPases, through the coordinated dynamics of intracellular trafficking along cytoskeletal pathways, determine the cell surface presentation of proteins and the [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par une perturbation de l'expression du gène DICER1 dans le processus métastatique d'un cancer du côlon

Impaired DICER1 function promotes stemness and metastasis in colon cancer

Iliou, M. S. ; da Silva-Diz, V. ; Carmona, F. J. ; Ramalho-Carvalho, J. ; Heyn, H. ; Villanueva, A. ; Munoz, P. ; Esteller, M.

Disruption of microRNA (miRNA) expression patterns is now being recognized as a hallmark of human cancer. The causes of these altered profiles are diverse, and, among them, we found the existence of defects in the miRNA processing machinery. However, little is known about how these alterations affect the biology of the underlying tumors. Herein, we show that colorectal cancer cells with an impairment in DICER1, a major miRNA biogenesis gene, undergo enrichment of tumor stemness features and an [...]