A partir de données génomiques issues du projet The Cancer Genome Atlas et portant sur 14 types de cancer, cette étude met en évidence le rôle joué par des cytidines désaminases APOBEC dans les processus de mutagenèse

An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers

Roberts, Steven A. ; Lawrence, Michael S. ; Klimczak, Leszek J. ; Grimm, Sara A. ; Fargo, David ; Stojanov, Petar ; Kiezun, Adam ; Kryukov, Gregory V. ; Carter, Scott L. ; Saksena, Gordon ; Harris, Shawn ; Shah, Ruchir R. ; Resnick, Michael A. ; Getz, Gad ; Gordenin, Dmitry A.

Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to [...]

A partir de données d'expression de gènes portant sur 19 types de cancer, cette étude met en évidence le rôle joué par la cytidine désaminase APOBEC3B dans les processus de mutagenèse

Evidence for APOBEC3B mutagenesis in multiple human cancers

Burns, Michael B. ; Temiz, Nuri A. ; Harris, Reuben S.

Thousands of somatic mutations accrue in most human cancers, and their causes are largely unknown. We recently showed that the DNA cytidine deaminase APOBEC3B accounts for up to half of the mutational load in breast carcinomas expressing this enzyme. Here we address whether APOBEC3B is broadly responsible for mutagenesis in multiple tumor types. We analyzed gene expression data and mutation patterns, distributions and loads for 19 different cancer types, with over 4,800 exomes and 1,000,000 [...]

Menée initialement sur 12 échantillons tumoraux prélevés sur des patients atteints d'un mélanome primitif de l'uvée, puis sur 105 échantillons complémentaires, cette étude identifie des mutations du gène SF3B1 en association avec un épissage alternatif différentiel des gènes ABCC5 et UQCC

SF3B1 mutations are associated with alternative splicing in uveal melanoma

Furney, Simon J. ; Pedersen, Malin ; Gentien, David ; Dumont, Amaury G. ; Rapinat, Audrey ; Desjardins, Laurence ; Turajlic, Samra ; Piperno-Neumann, Sophie ; de la Grange, Pierre ; Roman-Roman, Sergio ; Stern, Marc-Henri ; Marais, Richard

Uveal melanoma, the most common eye malignancy causes severe visual morbidity and is fatal in about 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we performed SNP arrays and whole genome sequencing on 12 primary uveal melanomas. We observed only ~2000 predicted somatic single nucleotide variants per tumor and low levels of aneuploidy. We did not observe [...]

A partir d'échantillons prélevés à des phases différentes de la maladie sur une cohorte de 306 patients atteints d'un myélome multiple, cette étude française suggère que la translocation t(4;14) n'est pas un événement premier et montre qu'elle peut être présente dans une petite population clonale lors du diagnostic ou d'une récidive

The translocation t(4;14) can be present only in minor subclones in multiple myeloma

Hebraud, Benjamin ; Caillot, Denis ; Corre, Jill ; Marit, Gérald ; Hulin, Cyrille ; Leleu, Xavier ; Lodé, Laurence ; Wetterwald, Marc ; Dib, Mamoun ; Rodon, Philippe ; Voillat, Laurent ; Royer, Bruno ; VOOG, Eric ; Fitoussi, Olivier ; Stoppa, Anne-Marie ; Garderet, Laurent ; Kolb, Brigitte ; MAIGRE, Michel ; BOULLANGER, Nadine ; Allangba, Olivier ; Karlin, Lionel ; DAGUINDEAU, Nicolas ; LEGROS, Laurence ; SOHN, Claudine ; JOUBERT, Marie-Veronique ; LENAIN, Pascal ; Facon, Thierry ; Attal, Michel ; Moreau, Philippe ; Avet-Loiseau, Hervé

Purpose: Although the translocation t(4;14) is supposed to be a primary event in multiple myeloma, we have been surprised to observe that in large relapse series of patients, the t(4;14) can be observed only in subpopulations of plasma cells, in contrast to what is seen at diagnosis. This observation raised the question of possible subclones harboring the translocation that would be observable only at the time of relapse. Experimental Design: To address this issue, we analyzed by FISH a cohort [...]

Menée sur 39 lignées cellulaires de cancer du pancréas et à l'aide de xénogreffes, cette étude identifie la présence de mutations inactivant le gène RNF43, puis montre que ces mutations induisent une dépendance des cellules tumorales à la signalisation Wnt

Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma

Jiang, Xiaomo ; Hao, Huai-Xiang ; Growney, Joseph D. ; Woolfenden, Steve ; Bottiglio, Cindy ; Ng, Nicholas ; Lu, Bo ; Hsieh, Mindy H. ; Bagdasarian, Linda ; Meyer, Ronald ; Smith, Timothy R. ; Avello, Monika ; Charlat, Olga ; Xie, Yang ; Porter, Jeffery A. ; Pan, Shifeng ; Liu, Jun ; McLaughlin, Margaret E. ; Cong, Feng

A growing number of agents targeting ligand-induced Wnt/β-catenin signaling are being developed for cancer therapy. However, clinical development of these molecules is challenging because of the lack of a genetic strategy to identify human tumors dependent on ligand-induced Wnt/β-catenin signaling. Ubiquitin E3 ligase ring finger 43 (RNF43) has been suggested as a negative regulator of Wnt signaling, and mutations of RNF43 have been identified in various tumors, including cystic pancreatic [...]

Cet article passe en revue les travaux récents sur le rôle du complexe DREAM dans la surexpression de divers gènes fréquemment observée dans les cancers à pronostic défavorable

The DREAM complex: master coordinator of cell cycle-dependent gene expression

Sadasivam, Subhashini ; DeCaprio, James A.

The dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex provides a previously unsuspected unifying role in the cell cycle by directly linking p130, p107, E2F, BMYB and forkhead box protein M1. DREAM mediates gene repression during the G0 phase and coordinates periodic gene expression with peaks during the G1/S and G2/M phases. Perturbations in DREAM complex regulation shift the balance from quiescence towards proliferation and contribute to the increased mitotic gene [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle de suppresseur de tumeurs joué par le gène MYBL2 dans les syndromes myélodysplasiques et les néoplasies myéloprolifératives

MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy

Stefan Heinrichs ; Lillian F Conover ; Carlos E Bueso-Ramos ; Outi Kilpivaara ; Kristen Stevenson ; Donna Neuberg ; Mignon L Loh ; Wen-Shu Wu ; Scott J Rodig ; Guillermo Garcia-Manero ; Hagop M Kantarjian ; A Thomas Look

A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20–30% of normal levels in [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en régulant l'activation de p53, le gène BACH2 inhibe la transformation leucémique

BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint

Swaminathan, Srividya ; Huang, Chuanxin ; Geng, Huimin ; Chen, Zhengshan ; Harvey, Richard ; Kang, Huining ; Ng, Carina ; Titz, Bjorn ; Hurtz, Christian ; Sadiyah, Mohammed Firas ; Nowak, Daniel ; Thoennissen, Gabriela B. ; Rand, Vikki ; Graeber, Thomas G. ; Koeffler, H. Phillip ; Carroll, William L. ; Willman, Cheryl L. ; Hall, Andrew G. ; Igarashi, Kazuhiko ; Melnick, Ari ; Müschen, Markus

The B cell–specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. After productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'axe de signalisation ZIP4-CREB-miR-373 dans la croissance d'une tumeur du pancréas

A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth

Zhang, Yuqing ; Yang, Jingxuan ; Cui, Xiaobo ; Chen, Yong ; Zhu, Vivian F. ; Hagan, John P. ; Wang, Huamin ; Yu, Xianjun ; Hodges, Sally E. ; Fang, Jing ; Chiao, Paul J. ; Logsdon, Craig D. ; Fisher, William E. ; Brunicardi, F. Charles ; Chen, Changyi ; Yao, Qizhi ; Fernandez-Zapico, Martin E. ; Li, Min

Changes in the intracellular levels of the essential micronutrient zinc have been implicated in multiple diseases including pancreatic cancer; however, the molecular mechanism is poorly understood. Here, we report a novel mechanism where increased zinc mediated by the zinc importer ZIP4 transcriptionally induces miR-373 in pancreatic cancer to promote tumour growth. Reporter, expression and chromatin immunoprecipitation assays demonstrate that ZIP4 activates the zinc-dependent transcription [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes épigénétiques inhibant la fonction de suppression de tumeurs exercée par le gène NTRK3 dans le cancer colorectal

NTRK3 Is a Potential Tumor Suppressor Gene Commonly Inactivated by Epigenetic Mechanisms in Colorectal Cancer

Luo, Yanxin ; Kaz, Andrew M. ; Kanngurn, Samornmas ; Welsch, Piri ; Morris, Shelli M. ; Wang, Jianping ; Lutterbaugh, James D. ; Markowitz, Sanford D. ; Grady, William M.

NTRK3 is a member of the neurotrophin receptor family and regulates cell survival. It appears to be a dependence receptor, and thus has the potential to act as an oncogene or as a tumor suppressor gene. NTRK3 is a receptor for NT-3 and when bound to NT-3 it induces cell survival, but when NT-3 free, it induces apoptosis. We identified aberrantly methylated NTRK3 in colorectal cancers through a genome-wide screen for hypermethylated genes. This discovery led us to assess whether NTRK3 could be a [...]

Cet article passe en revue les travaux récents sur les mécanismes d'échappement au système immunitaire de cellules tumorales en liaison avec des anomalies dans les gènes impliqués dans le processus appelé "machinerie de traitement et de présentation des antigènes"

MHC Class I Antigen Processing and Presenting Machinery: Organization, Function, and Defects in Tumor Cells

Leone, Patrizia ; Shin, Eui-Cheol ; Perosa, Federico ; Vacca, Angelo ; Dammacco, Franco ; Racanelli, Vito

The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to all CD8+ T-cell adaptive immune responses, including those against tumors. The generation of peptides and their loading on MHC class I molecules is a multistep process involving multiple molecular species that constitute the so-called antigen processing and presenting machinery (APM). The majority of class I peptides begin as proteasome degradation products of cytosolic proteins. Once [...]

Cet article passe en revue les travaux récents sur le rôle des chimiokines inflammatoires dans le processus métastatique

Inflammatory chemokines and metastasis-tracing the accessory

Borsig, L. ; Wolf, M. J. ; Roblek, M. ; Lorentzen, A. ; Heikenwalder, M.

The tumor microenvironment consists of stromal cells and leukocytes that contribute to cancer progression. Cross-talk between tumor cells and their microenvironment is facilitated by a variety of soluble factors, including growth factors and cytokines such as chemokines. Due to a wide expression of chemokine receptors on cells in the tumor microenvironment, including tumor cells, chemokines affect various processes such as leukocyte recruitment, angiogenesis, tumor cell survival, tumor cell [...]

Cet article passe en revue le rôle du micro-environnement tumoral dans le développement d'un lymphome hodgkinien classique

The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component

Liu, Yuxuan ; Sattarzadeh, Ahmad ; Diepstra, Arjan ; Visser, Lydia ; van den Berg, Anke

Classical Hodgkin lymphoma (cHL) is characterized by a minority of tumor cells derived from germinal center B-cells and a vast majority of non-malignant reactive cells. The tumor cells show a loss of B-cell phenotype including lack of the B-cell receptor, which makes the tumor cells vulnerable to apoptosis. To overcome this threat, tumor cells and their precursors depend on anti-apoptotic and growth stimulating factors that are obtained via triggering of multiple membrane receptors. In [...]

A partir d'échantillons tumoraux prélevés sur 74 patients atteints d'une tumeur osseuse à cellules géantes, cette étude met en évidence des mécanismes par lesquels l'interleukine 17A favorise la croissance tumorale

IL-17A Stimulates the Progression of Giant Cell Tumors of Bone

Wang, Yan ; xu, meng ; song, zhi-gang ; Xu, Cheng-Xiong ; rong, guang-hua ; fan, ke-xing ; cheng, ji-ying ; Zhang, Wei ; JIA, JIN-PENG ; HAN, GANG ; Wang, Wei ; CHAI, WEI ; LIANG, WEN-TAO ; BI, WEN-ZHI

Purpose:Giant cell tumors of bone (GCTBs) exhibit aggressive bone lytic behavior. Studies have shown that interleukin 17A (IL-17A) is involved pathological bone resorption in various skeletal disorders. Thus, we have investigated the role of IL-17A in GCTBs. Experimental Design:We evaluated the progression of GCTBs using Campanacci grading and Enneking staging systems in 74 GCTB patients. The expression of IL-17A and the IL-17A receptor A (IL-17RA) was assessed in GCTB tissues and in both [...]

Cet article passe en revue les travaux récents sur le rôle du système immunitaire dans le développement et la progression d'un adénocarcinome canalaire du pancréas

The immune network in pancreatic cancer development and progression

Wormann, S. M. ; Diakopoulos, K. N. ; Lesina, M. ; Algul, H.

The presence of stromal desmoplasia is a hallmark of spontaneous pancreatic ductal adenocarcinoma, forming a unique microenvironment that comprises many cell types. Only recently, the immune system has entered the pathophysiology of pancreatic ductal adenocarcinoma development. Tumor cells in the pancreas seem to dysbalance the immune system, thus facilitating spontaneous cancer development. This review will try to assemble all relevant data to demonstrate the implications of the immune network [...]

Menée à l'aide de xénogreffes de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels une surexpression de la tyrosine kinase PTK6 favorise une transition épithélio-mésenchymateuse

PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer

Zheng, Yu ; Wang, Zebin ; Bie, Wenjun ; Brauer, Patrick M. ; Perez White, Bethany E. ; Li, Jing ; Nogueira, Veronique ; Raychaudhuri, Pradip ; Hay, Nissim ; Tonetti, Debra A. ; Macias, Virgilia ; Kajdacsy-Balla, Andre ; Tyner, Angela L.

The intracellular tyrosine kinase PTK6 lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le récepteur couplé aux protéines 120 favorise le développement d'un cancer colorectal

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

Wu, Q. ; Wang, H. ; Zhao, X. ; Shi, Y. ; Jin, M. ; Wan, B. ; Xu, H. ; Cheng, Y. ; Ge, H. ; Zhang, Y.

G-protein-coupled receptor 120 (GPR120) functions as a receptor for unsaturated long-chain free fatty acids and has an important role in regulating lipid and glucose metabolism. However, a role for GPR120 in the development of tumors has not yet been clarified. Here, we show that GPR120 signaling promotes angiogenic switching and motility of human colorectal carcinoma (CRC) cells. We show that the expression of GPR120 is significantly induced in CRC tissues and cell lines, which is associated [...]

Menée sur des échantillons prélevés sur 18 patients atteints d'une colite ulcéreuse (9 avec une dysplasie de haut grade ou un cancer, 9 témoins), cette étude met en évidence le rôle joué par des anomalies mitochondriales dans la tumorigenèse

Mitochondria and Tumor Progression in Ulcerative Colitis

Ussakli, Cigdem Himmetoglu ; Ebaee, Anoosheh ; Binkley, Jennifer ; Brentnall, Teresa A. ; Emond, Mary J. ; Rabinovitch, Peter S. ; Risques, Rosa Ana

Background The role of mitochondria in cancer is poorly understood. Ulcerative colitis (UC) is an inflammatory bowel disease that predisposes to colorectal cancer and is an excellent model to study tumor progression. Our goal was to characterize mitochondrial alterations in UC tumorigenesis. Methods Nondysplastic colon biopsies from UC patients with high-grade dysplasia or cancer (progressors; n = 9) and UC patients dysplasia free (nonprogressors; n = 9) were immunostained for cytochrome C [...]