Menée sur des échantillons de tissu tumoral et de tissu sain prélevés sur deux patients singapouriens atteints d'un cancer de l'estomac, puis sur des données portant sur 134 cas complémentaires, cette étude de séquençage du génome entier identifie de fréquentes mutations de trois gènes dans les cancers gastriques associés à une instabilité microsatellitaire

Whole-genome reconstruction and mutational signatures in gastric cancer

Nagarajan, Niranjan ; Bertrand, Denis ; Hillmer, Axel ; Zang, Zhi Jiang ; Yao, Fei ; Jacques, Pierre-Etienne ; Teo, Audrey ; Cutcutache, Ioanna ; Zhang, Zhenshui ; Lee, Wah Heng ; Sia, Yee Yen ; Gao, Song ; Ariyaratne, Pramila ; Ho, Andrea ; Woo, Xing Yi ; Veeravali, Lavanya ; Ong, Choon Kiat ; Deng, Niantao ; Desai, Kartiki ; Khor, Chiea Chuen ; Hibberd, Martin ; Shahab, Atif ; Rao, Jaideepraj ; Wu, Mengchu ; Teh, Ming ; Zhu, Feng ; Chin, Sze Yung ; Pang, Brendan ; So, Jimmy ; Bourque, Guillaume ; Soong, Richie ; Sung, Wing-Kin ; Teh, Bin Tean ; Rozen, Steven ; Ruan, Xiaoan ; Yeoh, Khay Guan ; Tan, Patrick ; Ruan, Yijun

BACKGROUND:Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively-parallel short read and DNA-PET sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability. RESULTS:Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a [...]

Cette étude passe en revue les travaux récents sur le rôle des mutations du gène BRAF dans les mélanomes et les cancers du côlon-rectum

BRAF mutations in melanoma and colorectal cancer: A single oncogenic mutation with different tumour phenotypes and clinical implications

Sclafani, F. ; Gullo, G. ; Sheahan, K. ; Crown, J.

BRAF is an oncogene encoding a serine–threonine protein kinase involved in the MAPK signalling cascade. BRAF acts as direct effector of RAS and through the activation of MEK, promotes tumour growth and survival. Approximately, 8% of cancers carry a BRAF mutation. However, the prevalence of this mutation varies significantly across different tumour types. There has been increasing interest in the specific role of BRAF mutations in cancer growth and progression over the last few years, especially [...]

A partir d'échantillons prélevés sur 235 patients pédiatriques atteints d'un cancer, cette étude de séquençage du génome entier analyse la fréquence des altérations du contenu des télomères en fonction des types de cancer

Assessing telomeric DNA content in pediatric cancers using whole-genome sequencing data

Parker, Matthew ; Chen, Xiang ; Bahrami, Armita ; Dalton, James ; Rusch, Michael ; Wu, Gang ; Easton, John ; Cheung, Nai-Kong ; Dyer, Michael ; Mardis, Elaine ; Wilson, Richard ; Mullighan, Charles ; Gilbertson, Richard ; Baker, Suzanne ; Zambetti, Gerard ; Ellison, David ; Downing, James ; Zhang, Jinghui

BACKGROUND:Telomeres are the protective arrays of tandem TTAGGG sequence and associated proteins at the termini of chromosomes. Telomeres shorten at each cell division due to the end-replication problem and are maintained above a critical threshold in malignant cancer cells to prevent cellular senescence or apoptosis. With the recent advances in massive parallel sequencing, assessing telomere content in the context of other cancer genomic aberrations becomes an attractive possibility. We [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la thrombopoïétine stimule la réparation de dégâts causés par des rayonnements ionisants à l'ADN des cellules souches hématopoïétiques

Thrombopoietin-Increased DNA-PK-Dependent DNA Repair Limits Hematopoietic Stem and Progenitor Cell Mutagenesis in Response to DNA Damage

de Laval, Bérengère ; Pawlikowska, Patrycja ; Petit-Cocault, Laurence ; Bilhou-Nabera, Chrystèle ; Aubin-Houzelstein, Geneviève ; Souyri, Michèle ; Pouzoulet, Frédéric ; Gaudry, Murielle ; Porteu, Françoise

DNA double-strand breaks (DSBs) represent a serious threat for hematopoietic stem cells (HSCs). How cytokines and environmental signals integrate the DNA damage response and contribute to HSC-intrinsic DNA repair processes remains unknown. Thrombopoietin (TPO) and its receptor, Mpl, are critical factors supporting HSC self-renewal and expansion. Here, we uncover an unknown function for TPO-Mpl in the regulation of DNA damage response. We show that DNA repair following

Cet article passe en revue les travaux récents sur le rôle des transposons et rétrotransposons dans les processus de cancérogenèse

Transposable elements and human cancer: A causal relationship?

Chénais, Benoît

Transposable elements are present in almost all genomes including that of humans. These mobile DNA sequences are capable of invading genomes and their impact on genome evolution is substantial as they contribute to the genetic diversity of organisms. The mobility of transposable elements can cause deleterious mutations, gene disruption and chromosome rearrangements that may lead to several pathologies including cancer. This mini-review aims to give a brief overview of the relationship that [...]

Menée in vitro, cette étude met en évidence un mécanisme impliquant une activation épigénétique à longue portée de régions du génome riches en oncogènes

Regional Activation of the Cancer Genome by Long-Range Epigenetic Remodeling

Bert, Saul A ; Robinson, Mark D ; Strbenac, Dario ; Statham, Aaron L ; Song, Jenny Z ; Hulf, Toby ; Sutherland, Robert L ; Coolen, Marcel W ; Stirzaker, Clare ; Clark, Susan J

Epigenetic gene deregulation in cancer commonly occurs through chromatin repression and promoter hypermethylation of tumor-associated genes. However, the mechanism underpinning epigenetic-based gene activation in carcinogenesis is still poorly understood. Here, we identify a mechanism of domain gene deregulation through coordinated long-range epigenetic activation (LREA) of regions that typically span 1 Mb and harbor key oncogenes, microRNAs, and cancer biomarker genes. Gene promoters within [...]

Cet article passe en revue les travaux récents sur le rôle des protéines arginines méthyltransférases dans les cancers

Protein arginine methyltransferases and cancer

Yang, Yanzhong ; Bedford, Mark T.

There are nine protein arginine methyltransferases (PRMTs) encoded in mammalian genomes, the protein products of which catalyse three types of arginine methylation — monomethylation and two types of dimethylation. Protein arginine methylation is an abundant modification that has been implicated in signal transduction, gene transcription, DNA repair and mRNA splicing, among others. Studies have only recently linked this modification to carcinogenesis and metastasis. Sequencing studies have not [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par le complexe transcriptionnel YAP1 dans la survie des cellules cancéreuses dépendant de la signalisation de la

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Rosenbluh, Joseph ; Nijhawan, Deepak ; Cox, Andrew G ; Li, Xingnan ; Neal, James T ; Schafer, Eric J ; Zack, Travis I ; Wang, Xiaoxing ; Tsherniak, Aviad ; Schinzel, Anna C ; Shao, Diane D ; Schumacher, Steven E ; Weir, Barbara A ; Vazquez, Francisca ; Cowley, Glenn S ; Root, David E ; Mesirov, Jill P ; Beroukhim, Rameen ; Kuo, Calvin J ; Goessling, Wolfram ; Hahn, William C

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Menée in vitro et à l'aide de modèles murins, cette étude met en évidence le rôle joué par p53 et l'interféron de type I dans le maintien d'une stabilité génétique et la prévention d'une tumorigenèse

p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs

Leonova, Katerina I. ; Brodsky, Leonid ; Lipchick, Brittany ; Pal, Mahadeb ; Novototskaya, Liliya ; Chenchik, Alex A. ; Sen, Ganes C. ; Komarova, Elena A. ; Gudkov, Andrei V.

Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53 cooperates with DNA methylation to maintain silencing of a large portion of the mouse genome. Massive transcription of major classes of short, interspersed nuclear elements (SINEs) B1 and B2, both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of noncoding RNAs was [...]

Menée in vitro, cette étude met en évidence une translocation du récepteur à activité tyrosine kinase ErbB2 dans les mitochondries de cellules cancéreuses et évalue son effet sur la résistance de ces cellules au trastuzumab

Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism

Ding, Yan ; Liu, Zixing ; Desai, Shruti ; Zhao, Yuhua ; Liu, Hao ; Pannell, Lewis K. ; Yi, Hong ; Wright, Elizabeth R. ; Owen, Laurie B. ; Dean-Colomb, Windy ; Fodstad, Oystein ; Lu, Jianrong ; LeDoux, Susan P. ; Wilson, Glenn L. ; Tan, Ming

It is well known that ErbB2, a receptor tyrosine kinase, localizes to the plasma membrane. Here we describe a novel observation that ErbB2 also localizes in mitochondria of cancer cells and patient samples. We found that ErbB2 translocates into mitochondria through association with mtHSP70. Additionally, mitochondrial ErbB2 (mtErbB2) negatively regulates mitochondrial respiratory functions. Oxygen consumption and activities of complexes of the mitochondrial electron transport chain were [...]

Menée à l'aide de modèles murins, cette étude met en évidence les différents rôles joués par l'intégrine α3β1 dans les stades précoce et tardif d'une tumorigenèse cutanée

Loss of integrin α3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells

Sachs, Norman ; Secades, Pablo ; van Hulst, Laura ; Kreft, Maaike ; Song, Ji-Ying ; Sonnenberg, Arnoud

Progression through the various stages of skin tumorigenesis is correlated with an altered expression of the integrin α3β1, suggesting that it plays an important role in the tumorigenic process. Using epidermis-specific Itga3 KO mice subjected to the 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate two-stage skin carcinogenesis protocol, we demonstrate that efficient tumor development is critically dependent on the presence of α3β1. In the absence of α3β1, tumor [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel une surexpression du récepteur EphA2 favorise la survie et le potentiel tumorigène des cellules souches de glioblastome

The EphA2 Receptor Drives Self-Renewal and Tumorigenicity in Stem-like Tumor-Propagating Cells from Human Glioblastomas

Binda, Elena ; Visioli, Alberto ; Giani, Fabrizio ; Lamorte, Giuseppe ; Copetti, Massimiliano ; Pitter, Ken L ; Huse, Jason T ; Cajola, Laura ; Zanetti, Nadia ; DiMeco, Francesco ; De Filippis, Lidia ; Mangiola, Annunziato ; Maira, Giulio ; Anile, Carmelo ; De Bonis, Pasquale ; Reynolds, Brent A ; Pasquale, Elena B ; Vescovi, Angelo L

In human glioblastomas (hGBMs), tumor-propagating cells with stem-like characteristics (TPCs) represent a key therapeutic target. We found that the EphA2 receptor tyrosine kinase is overexpressed in hGBM TPCs. Cytofluorimetric sorting into EphA2High and EphA2Low populations demonstrated that EphA2 expression correlates with the size and tumor-propagating ability of the TPC pool in hGBMs. Both ephrinA1-Fc, which caused EphA2 downregulation in TPCs, and siRNA-mediated knockdown of EPHA2 [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met én évidence un mécanisme par lequel une surexpression du gène de la mda-9/synténine favorise l'angiogenèse tumorale d'un mélanome

MDA-9/Syntenin and IGFBP-2 Promote Angiogenesis in Human Melanoma

Das, Swadesh K ; Bhutia, Sujit k ; Azab, Belal ; Kegelman, Timothy P. ; Peachy, Leyla ; Santhekadur, Prasanna K. ; Dasgupta, Santanu ; Dash, Rupesh ; Dent, Paul ; Grant, Steven ; Emdad, Luni ; Pellecchia, Maurizio ; Sarkar, Devanand ; Fisher, Paul

Melanoma differentiation associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacological approaches were employed to modify mda-9/syntenin expression in normal immortal [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par un long ARN non codant, MALAT1, dans le processus métastatique d'un cancer du poumon

The non-coding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells

Gutschner, Tony ; Hämmerle, Monika ; Eißmann, Moritz ; Hsu, Jeff ; Kim, Youngsoo ; Hung, Gene ; Revenko, Alexey S ; Arun, Gayatri ; Stentrup, Marion ; Groß, Matthias ; Zörnig, Martin ; MacLeod, A. Robert ; Spector, David L. ; Diederichs, Sven

The long non-coding RNA MALAT1, also known as MALAT-1 or NEAT2, is a highly conserved nuclear ncRNA and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using Zinc Finger Nucleases. The achieved 1000-fold MALAT1 silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel l'expression du gène STC1 dans les fibroblastes associés au cancer favorise le processus métastatique d'un cancer colorectal

STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer

Peña, Cristina ; Céspedes, María Virtudes ; Bradic Lindh, Maja ; Kiflemariam, Sara ; Mezheyeuski, Artur ; Edqvist, Per-Henrik ; Hägglöf, Christina ; Birgisson, Helgi ; Bojmar, Linda ; Jirström, Karin ; Sandström, Per ; Olsson, Eleonor ; Veerla, Srinivas ; Gallardo, Alberto ; Sjöblom, Tobias ; Chang, Andy C.-M ; Reddel, Roger R. ; Mangues, Ramón ; Augsten, Martin ; Ostman, Arne

PDGF receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAFs). Elevated expression of PDGF receptors on stromal CAFs are associated with metastasis and poor prognosis, but mechanism(s) that underlie this these connections are not understood. Here report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration [...]