Menée dans le cadre du projet "The Cancer Genome Atlas" sur 295 échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome de l'estomac, cette étude identifie, sur la base d'une analyse moléculaire, quatre sous-types différents susceptibles d'être utiles pour stratifier les patients et mener des essais de thérapies ciblées

Comprehensive molecular characterization of gastric adenocarcinoma

The Cancer Genome Atlas Research, Network

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme [...]

Menée sur des lignées cellulaires, cette étude suggère notamment que la mutation R175H du gène TP53 induit une plus forte instabilité génomique que les mutations V143A et R273H

Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres

Samassekou, Oumar ; Bastien, Nathalie ; Lichtensztejn, Daniel ; Yan, Ju ; Mai, Sabine ; Drouin, Régen

TP53 mutations are the most common mutations in human cancers, and TP53-R175H and TP53-R273H are the most frequent. The impact of these mutations on genomic instability after tumor initiation is still uncovered. To gain insight into this, we studied the effects of three specific TP53 mutants (TP53-V143A, TP53-R175H, and TP53-R273H) on genomic instability using four isogenic lines of LoVo cells. Multicolor fluorescence in situ hybridization (FISH), three-dimensional (3D) quantitative FISH [...]

Menée à partir d"échantillons tumoraux prélevés sur 20 patients atteints d'un myopéricytome, une tumeur rare périvasculaire, puis in vitro et in vivo, cette étude met en évidence la présence fréquente d'une mutation V600E du gène BRAF

Role of BRAFV600E in the First Preclinical Model of Multifocal Infiltrating Myopericytoma Development and Microenvironment

Sadow, Peter M. ; Priolo, Carmen ; Nanni, Simona ; Karreth, Florian A. ; Duquette, Mark ; Martinelli, Roberta ; Husain, Amjad ; Clohessy, John ; Kutzner, Heinz ; Mentzel, Thomas ; Carman, Christopher V. ; Farsetti, Antonella ; Henske, Elizabeth Petri ; Palescandolo, Emanuele ; MacConaill, Laura E. ; Chung, Seum ; Fadda, Guido ; Lombardi, Celestino Pio ; De Angelis, Antonina M. ; Durante, Oreste ; Parker, John A. ; Pontecorvi, Alfredo ; Dvorak, Harold F. ; Fletcher, Christopher ; Pandolfi, Pier Paolo ; Lawler, Jack ; Nucera, Carmelo

Myopericytoma (MPC) is a rare tumor with perivascular proliferation of pluripotent stem-cell–like pericytes. Although indolent, MPC may be locally aggressive with recurrent disease. The pathogenesis and diagnostic biomarkers of MPC are poorly understood. We discovered that 15% of benign MPCs (thyroid, skin; 3 of 20 samples) harbored BRAFWT/V600E; 33.3% (1 of 3 samples) of BRAFWT/V600E-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAFWT/V600E, were [...]

Menée sur des échantillons tumoraux prélevés sur 218 patients atteints d'un cancer de la prostate (105 Africains-Américains et 113 Caucasiens), cette étude compare la fréquence des réarrangements ERG, des délétions PTEN, des surexpressions de SPINK1 et des mutations SPOP entre les deux populations

Evidence for Molecular Differences in Prostate Cancer between African American and Caucasian Men

Khani, Francesca ; Mosquera, Juan Miguel ; Park, Kyung ; Blattner, Mirjam ; O'Reilly, Catherine ; MacDonald, Theresa Y ; Chen, Zhengming ; Srivastava, Abhishek ; Tewari, Ashutosh K ; Barbieri, Christopher E ; Rubin, Mark A ; Robinson, Brian D

Purpose: To compare the frequency of ERG rearrangement, PTEN deletion, SPINK1 overexpression, and SPOP mutation in prostate cancer in African American and Caucasian men. Experimental design: Dominant tumor nodules from radical prostatectomy specimens of 105 African American men (AAM) were compared to 113 dominant nodules from Caucasian men (CaM). Clinical and pathologic characteristics of the two groups were similar. SPINK1 overexpression was evaluated by immunohistochemistry, ERG rearrangement [...]

Menée sur deux patients atteints d'un cancer colorectal présentant des métastases hépatiques, cette étude de séquençage du génome entier compare le spectre des anomalies génomiques présentes dans les tumeurs primitives et dans les métastases

Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing

Xie, Tao ; Cho, Yong Beom ; Wang, Kai ; Huang, Donghui ; Hong, Hye Kyung ; Choi, Yoon-La ; Ko, Young Hyeh ; Nam, Do-Hyun ; Jin, Juyoun ; Yang, Heekyoung ; Fernandez, Julio ; Deng, Shibing ; Rejto, Paul A. ; Lee, Woo Yong ; Mao, Mao

Colorectal cancer (CRC) patients have poor prognosis after formation of distant metastasis. Understanding the molecular mechanisms by which genetic changes facilitate metastasis is critical for the development of targeted therapeutic strategies aimed at controlling disease progression while minimizing toxic side effects. A comprehensive portrait of somatic alterations in CRC and the changes between primary and metastatic tumors has yet to be developed. We performed whole genome sequencing of [...]

Menée sur 120 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un carcinome épidermoïde avancé de la tête et du cou, dont 42,5% étaient infectés par le papillomavirus humain (HPV), cette étude met en évidence des différences significatives, en fonction du statut HPV, dans le spectre des anomalies génomiques

Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas

Seiwert, Tanguy Y ; Zuo, Zhixiang ; Keck, Michaela K ; Khattri, Arun ; Pedamallu, Chandra Sekhar ; Stricker, Thomas P ; Brown, Christopher D ; Pugh, Trevor J ; Stojanov, Petar ; Cho, Juok ; Lawrence, Michael ; Getz, Gad ; Bragelmann, Johannes ; DeBoer, Rebecca ; Weichselbaum, Ralph R. ; Langerman, Alexander ; Portugal, Louis D ; Blair, Elizabeth A ; Stenson, Kerstin M ; Lingen, Mark W. ; Cohen, Ezra EW ; Vokes, Everett E. ; White, Kevin P. ; Hammerman, Peter S.

Purpose: The genetic differences between Human papilloma Virus (HPV)-positive and negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. In order to identify differential biology and novel therapeutic targets for both entities we determined mutations and copy number aberrations in a large cohort of locoregionally-advanced HNSCC. Experimental Design: We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (42.5% [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par une anomalie de la régulation épigénétique du gène p16lnk4a dans le développement d'une tumeur et la progression maligne

Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice

Yu, Da-Hai ; Waterland, Robert A. ; Zhang, Pumin ; Schady, Deborah ; Chen, Miao-Hsueh ; Guan, Yongtao ; Gadkari, Manasi ; Shen, Lanlan

Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated [...]

Menée in vitro et in vivo, cette étude identifie des mécanismes par lesquels une hélicase (elF4A) régule l'expression d'un ensemble d'oncogènes dans les leucémies aiguës lymphoblastiques

RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

Wolfe, Andrew L. ; Singh, Kamini ; Zhong, Yi ; Drewe, Philipp ; Rajasekhar, Vinagolu K. ; Sanghvi, Viraj R. ; Mavrakis, Konstantinos J. ; Jiang, Man ; Roderick, Justine E. ; Van der Meulen, Joni ; Schatz, Jonathan H. ; Rodrigo, Christina M. ; Zhao, Chunying ; Rondou, Pieter ; de Stanchina, Elisa ; Teruya-Feldstein, Julie ; Kelliher, Michelle A. ; Speleman, Frank ; Porco, John A. ; Pelletier, Jerry ; Ratsch, Gunnar ; Wendel, Hans-Guido

The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une histone méthyltransférase (MLL4), connue pour exercer une fonction de suppresseur de tumeurs dans les lymphomes B, favorise le développement d'une forme aggressive de leucémie myéloïde aiguë présentant l'oncogène MLL-AF9

DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier

Santos, Margarida A. ; Faryabi, Robert B. ; Ergen, Aysegul V. ; Day, Amanda M. ; Malhowski, Amy ; Canela, Andres ; Onozawa, Masahiro ; Lee, Ji-Eun ; Callén, Elsa ; Gutierrez-Martinez, Paula ; Chen, Hua-Tang ; Wong, Nancy ; Finkel, Nadia ; Deshpande, Aniruddha ; Sharrow, Susan ; Rossi, Derrick J. ; Ito, Keisuke ; Ge, Kai ; Aplan, Peter D. ; Armstrong, Scott A. ; Nussenzweig, André

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma, is required for stem-cell activity and an aggressive form of [...]

A partir de 103 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients danois atteints d'un cancer colorectal, cette étude de séquençage de l'ARN identifie un ensemble d'anomalies dans la régulation en cis de 71 gènes et suggère que ces anomalies jouent un rôle important dans la tumorigenèse

Putative cis-regulatory drivers in colorectal cancer

Ongen, Halit ; Andersen, Claus L. ; Bramsen, Jesper B. ; Oster, Bodil ; Rasmussen, Mads H. ; Ferreira, Pedro G. ; Sandoval, Juan ; Vidal, Enrique ; Whiffin, Nicola ; Planchon, Alexandra ; Padioleau, Ismael ; Bielser, Deborah ; Romano, Luciana ; Tomlinson, Ian ; Houlston, Richard S. ; Esteller, Manel ; Orntoft, Torben F. ; Dermitzakis, Emmanouil T.

The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. To better characterize colorectal cancer (CRC) development we conducted an RNA-sequencing experiment of 103 matched tumour and normal colon mucosa samples from Danish CRC patients, 90 of which were germline-genotyped. By investigating allele-specific expression (ASE) we show that the germline genotypes remain important [...]

Cet article passe en revue les travaux récents sur les mécanismes moléculaires associés à la présence de fusions impliquant le gène TFE3 ou le gène TFEB dans les carcinomes à cellules rénales

Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers

Kauffman, Eric C. ; Ricketts, Christopher J. ; Rais-Bahrami, Soroush ; Yang, Youfeng ; Merino, Maria J. ; Bottaro, Donald P. ; Srinivasan, Ramaprasad ; Linehan, W. Marston

Despite nearly two decades passing since the discovery of gene fusions involving TFE3 or TFEB in sporadic renal cell carcinoma (RCC), the molecular mechanisms underlying the renal-specific tumorigenesis of these genes remain largely unclear. The recently published findings of The Cancer Genome Atlas Network reported that five of the 416 surveyed clear cell RCC tumours (1.2%) harboured SFPQ-TFE3 fusions, providing further evidence for the importance of gene fusions. A total of five TFE3 gene [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en interagissant avec la protéine BRCA1, la protéine Abraxas exerce une fonction de suppresseur de tumeurs

The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression

Castillo, Andy ; Paul, Atanu ; Sun, Baohua ; Huang, Ting Hsiang ; Wang, Yucai ; Yazinski, Stephanie A ; Tyler, Jessica ; Li, Lei ; You, M.  James ; Zou, Lee ; Yao, Jun ; Wang, Bin

Germline mutations of BRCA1 confer hereditary susceptibility to breast and ovarian cancer. However, somatic mutation of BRCA1 is infrequent in sporadic breast cancers. The BRCA1 protein C terminus (BRCT) domains interact with multiple proteins and are required for BRCA1's tumor-suppressor function. In this study, we demonstrated that Abraxas, a BRCA1 BRCT domain-interacting protein, plays a role in tumor suppression. Abraxas exerts its function through binding to BRCA1 to regulate DNA repair [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en réduisant l'expression de la E-cadhérine, une isoforme de p53 favorise la transition épithélio-mésenchymateuse et accroît la motilité et les propriétés invasives des cellules tumorales

p53-psi is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state

Senturk, Serif ; Yao, Zhan ; Camiolo, Matthew ; Stiles, Brendon ; Rathod, Trushar ; Walsh, Alice M. ; Nemajerova, Alice ; Lazzara, Matthew J. ; Altorki, Nasser K. ; Krainer, Adrian ; Moll, Ute M. ; Lowe, Scott W. ; Cartegni, Luca ; Sordella, Raffaella

Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3′ splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target [...]

Menée à l'aide de xénogreffes de mélanome sur des poissons zèbres, cette étude met en évidence un phénomène appelé "invasion coopérative", par lequel des sous-populations cellulaires hétérogènes coopèrent pour favoriser la progression tumorale

Heterogeneous Tumor Subpopulations Cooperate to Drive Invasion

Chapman, Anna ; Fernandez del Ama, Laura ; Ferguson, Jennifer ; Kamarashev, Jivko ; Wellbrock, Claudia ; Hurlstone, Adam

Clonal selection and transcriptional reprogramming (e.g., epithelial-mesenchymal transition or phenotype switching) are the predominant theories thought to underlie tumor progression. However, a “division of labor” leading to cooperation among tumor-cell subpopulations could be an additional catalyst of progression. Using a zebrafish-melanoma xenograft model, we found that in a heterogeneous setting, inherently invasive cells, which possess protease activity and deposit extracellular matrix [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la protéine ADAM9 favorise la formation de métastases cérébrales d'une tumeur pulmonaire

ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway

Lin, Chen-Yuan ; Chen, Hung-Jen ; Huang, Cheng-Chung ; Lai, Liang-Chuan ; Lu, Tzu-Pin ; Tseng, Guan-Chin ; Kuo, Ting-Ting ; Kuok, Qian-Yu ; Hsu, Jennifer L. ; Sung, Shian-Ying ; Hung, Mien-Chie ; Sher, Yuh-Pyng

The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the pro-migratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une surexpression du récepteur TLR7 favorise la progression d'un adénocarcinome du poumon

TLR7 promotes tumor progression, chemotherapy resistance and poor clinical outcomes in non-small cell lung cancer

Chatterjee, Saradiya ; Crozet, Lucile ; Damotte, Diane ; Iribarren, Kristina ; Schramm, Catherine ; Alifano, Marco ; Lupo, Audrey ; Cherfils-Vicini, Julien ; Goc, Jeremy ; Katsahian, Sandrine ; Younes, Mohamad ; Dieu-Nosjean, Marie-Caroline ; Fridman, Wolf-Herman ; Sautès-Fridman, Catherine ; Cremer, Isabelle

Toll-Like Receptors (TLR) recognize pathogen molecules and danger-associated signals which stimulate inflammatory processes. TLR have been studied mainly in antigen-presenting cells where they exert important immune regulatory functions, but they are also expressed by epithelial tumor cells where they have been implicated in tumor progression. In this study, we demonstrate that the injection of TLR7 agonist in NOD/SCID mice, in C57BL/6 wild-type and TLR7 deficient mice grafted with lung [...]

Menée sur des échantillons de tumeurs primitives et de métastases prélevés sur 5 patients atteints d'un cancer de la prostate, cette étude met en évidence une hétérogénéité intratumorale dans la méthylation de l'ADN et le nombre de copies de gènes, puis montre comment cette hétérogénéité est le reflet de l'histoire naturelle des tumeurs

Intratumor DNA Methylation Heterogeneity Reflects Clonal Evolution in Aggressive Prostate Cancer

Brocks, David ; Assenov, Yassen ; Minner, Sarah ; Bogatyrova, Olga ; Simon, Ronald ; Koop, Christina ; Oakes, Christopher ; Zucknick, Manuela ; Lipka, Daniel Bernhard ; Weischenfeldt, Joachim ; Feuerbach, Lars ; Cowper-Sal·lari, Richard ; Lupien, Mathieu ; Brors, Benedikt ; Korbel, Jan ; Schlomm, Thorsten ; Tanay, Amos ; Sauter, Guido ; Gerhäuser, Clarissa ; Plass, Christoph

Despite much evidence on epigenetic abnormalities in cancer, it is currently unclear to what extent epigenetic alterations can be associated with tumors? clonal genetic origins. Here, we show that the prostate intratumor heterogeneity in DNA methylation and copy-number patterns can be explained by a unified evolutionary process. By assaying multiple topographically distinct tumor sites, premalignant lesions, and lymph node metastases within five cases of prostate cancer, we demonstrate that [...]