Menée en Chine à partir d'échantillons tumoraux prélevés sur 78 patients atteints d'un cancer de l'estomac, puis validée sur une cohorte complémentaire de 216 patients, cette étude identifie un ensemble de mutations spécifiques de cette population

Mutational landscape of gastric adenocarcinoma in Chinese: Implications for prognosis and therapy

Chen, Kexin ; Yang, Da ; Li, Xiangchun ; Sun, Baocun ; Song, Fengju ; Cao, Wenfeng ; Brat, Daniel J. ; Gao, Zhibo ; Li, Haixin ; Liang, Han ; Zhao, Yanrui ; Zheng, Hong ; Li, Miao ; Buckner, Jan ; Patterson, Scott D. ; Ye, Xiang ; Reinhard, Christoph ; Bhathena, Anahita ; Joshi, Deepa ; Mischel, Paul S. ; Croce, Carlo M. ; Wang, Yi Michael ; Raghavakaimal, Sreekumar ; Li, Hui ; Lu, Xin ; Pan, Yang ; Chang, Han ; Ba, Sujuan ; Luo, Longhai ; Cavenee, Webster K. ; Zhang, Wei ; Hao, Xishan

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC [...]

A partir de données d'expression de gènes issues de 16 172 échantillons tumoraux prélevés sur des patients atteints d'un cancer, cette étude met en évidence une association entre des anomalies du nombre de copies de l'ADN et les niveaux d'expression d'un ensemble de gènes

Gene expression analysis identifies global gene dosage sensitivity in cancer

Fehrmann, Rudolf S. N. ; Karjalainen, Juha M. ; Krajewska, Malgorzata ; Westra, Harm-Jan ; Maloney, David ; Simeonov, Anton ; Pers, Tune H. ; Hirschhorn, Joel N. ; Jansen, Ritsert C. ; Schultes, Erik A. ; van Haagen, Herman H. H. B. M. ; de Vries, Elisabeth G. E. ; te Meerman, Gerard J. ; Wijmenga, Cisca ; van Vugt, Marcel A. T. M. ; Franke, Lude

Many cancer-associated somatic copy number alterations (SCNAs) are known. Currently, one of the challenges is to identify the molecular downstream effects of these variants. Although several SCNAs are known to change gene expression levels, it is not clear whether each individual SCNA affects gene expression. We reanalyzed 77,840 expression profiles and observed a limited set of 'transcriptional components' that describe well-known biology, explain the vast majority of variation in gene [...]

Menée sur deux lignées cellulaires de cancer du sein dont la seule différence génomique est constituée d'un changement de nucléotide dans un allèle du gène PI3KCA, cette étude met en évidence une importante réorganisation cellulaire induite par cette unique mutation

The butterfly effect in cancer: A single base mutation can remodel the cell

Hart, Jonathan R. ; Zhang, Yaoyang ; Liao, Lujian ; Ueno, Lynn ; Du, Lisa ; Jonkers, Marloes ; Yates, John R. ; Vogt, Peter K.

We have compared the proteome, transcriptome, and metabolome of two cell lines: the human breast epithelial line MCF-10A and its mutant descendant MCF-10A-H1047R. These cell lines are derived from the same parental stock and differ by a single amino acid substitution (H1047R) caused by a single nucleotide change in one allele of the PIK3CA gene, which encodes the catalytic subunit p110α of PI3K (phosphatidylinositol 3-kinase). They are considered isogenic. The H1047R mutation of PIK3CA is one [...]

Menée in vitro et in vivo, ainsi qu'à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un lymphome, cette étude met en évidence des mécanismes par lesquels, en coopération avec divers oncogènes, l'enzyme PRMT5 favorise le développement de la maladie

PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers

Li, Yan ; Chitnis, Nilesh ; Nakagawa, Hiroshi ; Kita, Yoshiaki ; Natsugoe, Shoji ; Yang, Yi ; Li, Zihai ; Wasik, Mariusz A ; Klein-Szanto, Andres J. P. ; Rustgi, Anil K. ; Diehl, J. Alan

Protein arginine transferase 5(PRMT5) has been implicated as a key modulator of lymphomagenesis. Whether PRMT5 has overt oncogenic function in the context of leukemia/lymphoma and whether it represents a therapeutic target remains to be established. We demonstrate that inactivation of PRMT5 inhibits colony-forming activity by multiple oncogenic-drivers including cyclin D1, c-MYC, NOTCH1 and MLL-AF9. Furthermore, we demonstrate that PRMT5 overexpression specifically cooperates with cyclin D1 to [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la protéine NOTCH exerce une fonction de suppresseur de tumeurs dans les cancers de la vessie

NOTCH pathway inactivation promotes bladder cancer progression

Maraver, Antonio ; Fernandez-Marcos, Pablo J. ; Cash, Timothy P. ; Méndez-Pertuz, Marinela ; Dueñas, Marta ; Maietta, Paolo ; Martinelli, Paola ; Muñoz-Martin, Maribel ; Martínez-Fernández, Mónica ; Cañamero, Marta ; Roncador, Giovanna ; Martínez-Torrecuadrada, Jorge L. ; Grivas, Dimitrios ; de la Pompa, Jose Luis ; Valencia, Alfonso ; Paramio, Jesus M. ; Real, Francisco X. ; Serrano, Manuel

NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial [...]

Menée in vitro, cette étude met en évidence des mécanismes permettant de rendre compte de l'existence, au sein d'une population de cellules cancéreuses, de l'hétérogénéité des capacités de prolifération des sous-populations clonales

A Mechanism for Asymmetric Cell Division Resulting in Proliferative Asynchronicity

Dey-Guha, Ipsita ; Alves, Cleidson P. ; Yeh, Albert C. ; Salony, ; Solé, Xavier ; Darp, Revati ; Ramaswamy, Sridhar

All cancers contain an admixture of rapidly and slowly proliferating cancer cells. This proliferative heterogeneity complicates the diagnosis and treatment of patients with cancer because slow proliferators are hard to eradicate, can be difficult to detect, and may cause disease relapse sometimes years after apparently curative treatment. While clonal selection theory explains the presence and evolution of rapid proliferators within cancer cell populations, the circumstances and molecular [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en favorisant le recrutement de macrophages associés aux tumeurs dans le micro-environnement tumoral, la surexpression du récepteur multi-fonctionnel RAGE favorise la croissance tumorale et le processus métastatique d'un cancer du sein triplement négatif

RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment

Nasser, Mohd W ; Wani, Nissar ; Ahirwar, Dinesh K ; Powell, Catherine A ; Ravi, Janani ; Elbaz, Mohamad M ; Zhao, Helong ; Padilla, Laura ; Zhang, Xiaoli ; Shilo, Konstantin ; Ostrowski, Michael C. ; Shapiro, Charles L ; Carson, William E. ; Ganju, Ramesh K

RAGE is a multi-functional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer cells, both in primary tumors and lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by [...]

Menée à l'aide de xénogreffes de glioblastome multiforme, cette étude met en évidence des mécanismes par lesquels, via le recrutement de macrophages associés aux tumeurs, la périostine secrétée par les cellules souches de gliome favorise la progression tumorale

Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth

Zhou, Wenchao ; Ke, Susan Q. ; Huang, Zhi ; Flavahan, William ; Fang, Xiaoguang ; Paul, Jeremy ; Wu, Ling ; Sloan, Andrew E. ; McLendon, Roger E. ; Li, Xiaoxia ; Rich, Jeremy N. ; Bao, Shideng

Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN [...]

Cet article passe en revue les méthodes permettant d'estimer les erreurs et les biais dans les données produites par les technologies de séquençage de l'ADN

Accounting for uncertainty in DNA sequencing data

O’Rawe, Jason A. ; Ferson, Scott ; Lyon, Gholson J.

Science is defined in part by an honest exposition of the uncertainties that arise in measurements and propagate through calculations and inferences, so that the reliabilities of its conclusions are made apparent. The recent rapid development of high-throughput DNA sequencing technologies has dramatically increased the number of measurements made at the biochemical and molecular level. These data come from many different DNA-sequencing technologies, each with their own platform-specific errors [...]

Cet article passe en revue les perspectives offertes par les travaux sur un modèle animal, le poisson zèbre, pour la recherche translationnelle en oncologie

Zebrafish: A New Companion for Translational Research in Oncology

Barriuso, Jorge ; Nagaraju, Raghavendar ; Hurlstone, Adam

In an era of high-throughput 'omic' technologies, the unprecedented amount of data that can be generated presents a significant opportunity but simultaneously an even greater challenge for oncologists trying to provide personalized treatment. Classically, pre-clinical testing of new targets and identification of active compounds against those targets has entailed the extensive use of established human cell lines, as well as genetically modified mouse tumor models. Patient-derived xenografts in [...]