A partir d'échantillons tumoraux prélevés sur une cohorte initiale de 112 patients atteints d'un sarcome d'Ewing, puis sur une cohorte complémentaire de 229 patients, cette étude met notamment en évidence la présence concomitante de mutations des gènes STAG2 et TP53 en association avec un pronostic défavorable

Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations

Tirode, Franck ; Surdez, Didier ; Ma, Xiaotu ; Parker, Matthew ; Le Deley, Marie Cecile ; Bahrami, Armita ; Zhang, Zhaojie ; Lapouble, Eve ; Grossetete-Lalami, Sandrine ; Rusch, Michael ; Reynaud, Stephanie ; Rio-Frio, Thomas ; Hedlund, Erin ; Wu, Gang ; Chen, Xiang ; Pierron, Gaëlle ; Oberlin, Odile ; Zaidi, Sakina ; Lemmon, Gordon ; Gupta, Pankaj ; Vadodaria, Bhavin ; Easton, John ; Gut, Marta ; Ding, Li ; Mardis, Elaine R ; Wilson, Richard K. ; Shurtleff, Sheila ; Laurence, Valérie ; Michon, Jean ; Marec-Bérard, Perrine ; Gut, Ivo ; Downing, James ; Dyer, Michael ; Zhang, Jinghui ; Delattre, Olivier

Ewing sarcoma (ES) is a primary bone tumor initiated by EWSR1-ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole genome sequencing of 112 ES samples and matched germline DNA. Overall, ES tumors had relatively few single nucleotides variants, indels, structural variants and copy number alterations. Apart from whole chromosome arm copy number changes, the most common somatic mutations were in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, [...]

Menée sur 198 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein triplement négatif, puis sur des données complémentaires issues de 7 articles publiés, cette étude met en évidence quatre sous-types cliniques de la maladie, définis par une analyse de nombres de copies de l'ADN

Comprehensive Genomic Analysis Identifies Novel Subtypes and Targets of Triple-negative Breast Cancer

Burstein, Matthew D. ; Tsimelzon, Anna ; Poage, Graham M. ; Covington, Kyle R ; Contreras, Alejandro ; Fuqua, Suzanne ; Savage, Michelle ; Osborne, C. Kent ; Hilsenbeck, Susan G. ; Chang, Jenny C ; Mills, Gordon B. ; Lau, Ching C ; Brown, Powel H.

Purpose: Genomic profiling studies suggest triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study we sought to define TNBC subtypes and identify subtype-specific markers and targets. Experimental Design: RNA and DNA profiling analyses were conducted on 198 TNBC tumors (ER-negativity defined as Allred Scale value ≤2) with >50% cellularity (discovery set: n=84; validation set: n=114) collected at Baylor College of Medicine. An external data set of 7 publically-accessible [...]

A partir d'échantillons tumoraux prélevés sur 79 patients atteints d'un mélanome métastatique, puis menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels le gène PTPRD exerce une fonction de suppresseur de tumeurs

Mutational and Functional Analysis of the Tumor-Suppressor PTPRD in Human Melanoma

Walia, Vijay ; Prickett, Todd D. ; Kim, Jung-Sik ; Gartner, Jared J. ; Lin, Jimmy C. ; Zhou, Ming ; Rosenberg, Steven A. ; Elble, Randolph C. ; Solomon, David A. ; Waldman, Todd ; Samuels, Yardena

Protein tyrosine phosphatases (PTPs) tightly regulate tyrosine phosphorylation essential for cell growth, adhesion, migration, and survival. We performed a mutational analysis of the PTP gene family in cutaneous metastatic melanoma and identified 23 phosphatase genes harboring somatic mutations. Among these, receptor-type tyrosine–protein phosphatase delta (PTPRD) was one of the most highly mutated genes, harboring 17 somatic mutations in 79 samples, a prevalence of 21.5%. Functional evaluation [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, lorsqu'il est surexprimé, le micro-ARN miR-100 réduit la capacité d'auto-renouvellement des cellules souches de cancer du sein

microRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development

Deng, Lu ; Shang, Li ; Bai, Shoumin ; Chen, Ji ; He, Xueyan ; Trevino, Rachel M ; Chen, Shanshan ; Li, Xiaoyan ; Meng, Xiaojie ; Yu, Bin ; Wang, Xiaolin ; Liu, Yajing ; McDermott, Sean P ; Ariazi, Alexa E. ; Ginestier, Christophe ; Ibarra, Ingrid ; Ke, Jia ; Luther, Tahra K ; Clouthier, Shawn G. ; Xu, Liang ; Shan, Ge ; Song, Erwei ; Yao, Herui ; Hannon, Gregory J ; Weiss, Stephen J ; Wicha, Max S. ; Liu, Suling

microRNAs are essential for self-renewal and differentiation of normal and malignant stem cells by regulating the expression of key stem cell regulatory genes. Here we report evidence implicating the microRNA100 (miR-100) in self-renewal of cancer stem-like cells (CSC). We found that miR-100 expression levels relate to the cellular differentiation state with lowest expression in cells displaying stem cell markers. Utilizing a tetracycline-inducible lentivirus to elevate expression of miR-100 in [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels une enzyme impliquée dans le métabolisme du glutamate, GLUD2, favorise la prolifération des cellules de gliomes présentant la mutation R132H du gène IDH1

Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma

Chen, Ruihuan ; Nishimura, Merry C. ; Kharbanda, Samir ; Peale, Frank ; Deng, Yuzhong ; Daemen, Anneleen ; Forrest, William F. ; Kwong, Mandy ; Hedehus, Maj ; Hatzivassiliou, Georgia ; Friedman, Lori S. ; Phillips, Heidi S.

Somatic mutation of isocitrate dehydrogenase 1 (IDH1) is now recognized as the most common initiating event for secondary glioblastoma, a brain tumor type arising with high frequency in the frontal lobe. A puzzling feature of IDH1 mutation is the selective manifestation of glioma as the only neoplasm frequently associated with early postzygotic occurrence of this genomic alteration. We report here that IDH1R132H exhibits a growth-inhibitory effect that is abrogated in the presence of glutamate [...]

A partir de données provenant d'expériences menées à l'aide de xénogreffes de tumeurs du sein, cette étude évalue les performances d'une modélisation mathématique du processus métastatique

Mathematical modeling of tumor growth and metastatic spreading: validation in tumor-bearing mice

Hartung, Niklas ; Mollard, Séverine ; Barbolosi, Dominique ; Benabdallah, Assia ; Chapuisat, Guillemette ; Henry, Gérard ; Giacometti, Sarah ; ILIADIS, Athanassios ; Ciccolini, Joseph ; Faivre, Christian ; HUBERT, Florence

Defining tumor stage at diagnosis is a pivotal point for clinical decisions regarding patient treatment strategies. In this respect, early detection of occult metastasis invisible to current imaging methods would have a major impact on best care and long-term survival. Mathematical models that describe metastatic spreading might estimate the risk of metastasis when no clinical evidence is available. In this study, we adapted a top-down model to make such estimates. The model was constituted by [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la tyrosine kinase Pyk2 favorise la progression d'un myélome multiple

Pyk2 promotes tumor progression in multiple myeloma

Zhang, Yu ; Moschetta, Michele ; Huynh, Daisy ; Tai, Yu-Tzu ; Zhang, Yong ; Zhang, Wenjing ; Mishima, Yuji ; Ring, Jennifer E. ; Tam, Winnie F. ; Xu, Qunli ; Maiso, Patricia ; Reagan, Michaela ; Sahin, Ilyas ; Sacco, Antonio ; Manier, Salomon ; Aljawai, Yosra ; Glavey, Siobhan ; Munshi, Nikhil C. ; Anderson, Kenneth C. ; Pachter, Jonathan ; Roccaro, Aldo M. ; Ghobrial, Irene M.

Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared to healthy individuals. By using loss-of-function approaches we defined that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell [...]

A partir de données issues du projet "The Cancer Genome Atlas" portant sur près de 7 000 échantillons tumoraux, cette étude évalue les performances d'une méthode permettant d'identifier les fusions de gènes

The landscape of kinase fusions in cancer

Stransky, Nicolas ; Cerami, Ethan ; Schalm, Stefanie ; Kim, Joseph L. ; Lengauer, Christoph

Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been characterized as extensively. Here we develop heuristics for reliably detecting gene fusion events in RNA-seq data and apply them to nearly 7,000 samples from The Cancer Genome Atlas. We thereby are able to discover several novel and [...]

Cet article passe en revue les travaux récents sur le rôle des micro-ARNs dans la régulation de la réponse antitumorale du système immunitaire

The Role of MicroRNAs in the Control of Innate Immune Response in Cancer

Jasinski-Bergner, Simon ; Mandelboim, Ofer ; Seliger, Barbara

Ligands for receptors of natural killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTL), such as the inhibitory nonclassical HLA-G, the activating stress-induced major histocompatibility complex class I-related antigens MICA and MICB, and/or the UL16-binding proteins (ULBPs), are often aberrantly expressed upon viral infection and neoplastic transformation, thereby preventing virus-infected or malignant-transformed cells from elimination by immune effector cells. Recently, it has been shown [...]

Cette étude évalue l'intérêt d'utiliser des allogreffes sur un modèle murin pour étudier l'évolution d'un cancer du poumon non à petites cellules et pour développer de nouvelles approches thérapeutiques

Modeling Lung Cancer Evolution and Pre-Clinical Response By Orthotopic Mouse Allografts

Ambrogio, Chiara ; Carmona, Francisco J. ; Vidal, August ; Falcone, Mattia ; Nieto, Patricia ; Romero, Octavio A ; Puertas, Sara ; Vizoso, Miguel ; Nadal, Ernest ; Poggio, Teresa ; Sanchez-Cespedes, Montserrat ; Esteller, Manel ; Mulero, Francisca ; Voena, Claudia ; Chiarle, Roberto ; Barbacid, Mariano ; Santamaria, David ; Villanueva, Alberto

Cancer evolution is a process that is still poorly understood due to the lack of versatile in vivo longitudinal studies. By generating murine Non-Small Cell Lung Cancer (NSCLC) orthoallobanks and paired primary cell lines, we provide a detailed description of an in vivo, time-dependent cancer malignization process. We identify the acquisition of metastatic dissemination potential, the selection of co-driver mutations and the appearance of naturally occurring intra-tumor heterogeneity, thus [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des origines cellulaires et génétiques différentes pour les diverses formes de carcinome de la vessie

Bladder cancers arise from distinct urothelial sub-populations

Van Batavia, Jason ; Yamany, Tammer ; Molotkov, Andrei ; Dan, Hanbin ; Mansukhani, Mahesh ; Batourina, Ekaterina ; Schneider, Kerry ; Oyon, Daniel ; Dunlop, Mark ; Wu, Xue-Ru ; Cordon-Cardo, Carlos ; Mendelsohn, Cathy

Bladder cancer is the sixth most common cancer in humans. This heterogeneous set of lesions including urothelial carcinoma (Uca) and squamous cell carcinoma (SCC) arise from the urothelium, a stratified epithelium composed of K5-expressing basal cells, intermediate cells and umbrella cells. Superficial Uca lesions are morphologically distinct and exhibit different clinical behaviours: carcinoma in situ (CIS) is a flat aggressive lesion, whereas papillary carcinomas are generally low-grade and [...]