Menée sur 77 patients atteints d'une forme rare de leucémie lymphocytaire T, cette étude identifie la présence fréquente de mutations du gène STAT3

Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia

Koskela, Hanna L.M. ; Eldfors, Samuli ; Ellonen, Pekka ; van Adrichem, Arjan J. ; Kuusanmäki, Heikki ; Andersson, Emma I. ; Lagström, Sonja ; Clemente, Michael J. ; Olson, Thomas ; Jalkanen, Sari E. ; Majumder, Muntasir Mamun ; Almusa, Henrikki ; Edgren, Henrik ; Lepistö, Maija ; Mattila, Pirkko ; Guinta, Kathryn ; Koistinen, Pirjo ; Kuittinen, Taru ; Penttinen, Kati ; Parsons, Alun ; Knowles, Jonathan ; Saarela, Janna ; Wennerberg, Krister ; Kallioniemi, Olli ; Porkka, Kimmo ; Loughran, Thomas P. ; Heckman, Caroline A. ; Maciejewski, Jaroslaw P. ; Mustjoki, Satu

Background: T-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T lymphocytes (CTLs) and often associated with autoimmune disorders and immune-mediated cytopenias. Methods: We used next-generation exome sequencing to identify somatic mutations in CTLs from an index patient with large granular lymphocytic leukemia. Targeted resequencing was performed in a well-characterized cohort of 76 patients with this [...]

Menée sur 50 échantillons tumoraux prélevés à l'autopsie sur des patients ayant été lourdement traités pour un cancer métastatique de la prostate résistant à la castration et sur 11 échantillons tumoraux prélevés sur des patients avant un traitement pour un cancer localisé de haut grade de la prostate, cette étude de séquençage des exons dresse le paysage des mutations associées à ce cancer et identifie des nouveaux mécanismes de dérégulation de la signalisation du récepteur des androgènes

The mutational landscape of lethal castration-resistant prostate cancer

Grasso, Catherine S. ; Wu, Yi-Mi ; Robinson, Dan R. ; Cao, Xuhong ; Dhanasekaran, Saravana M. ; Khan, Amjad P. ; Quist, Michael J. ; Jing, Xiaojun ; Lonigro, Robert J. ; Brenner, J. Chad ; Asangani, Irfan A. ; Ateeq, Bushra ; Chun, Sang Y. ; Siddiqui, Javed ; Sam, Lee ; Anstett, Matt ; Mehra, Rohit ; Prensner, John R. ; Palanisamy, Nallasivam ; Ryslik, Gregory A. ; Vandin, Fabio ; Raphael, Benjamin J. ; Kunju, Lakshmi P. ; Rhodes, Daniel R. ; Pienta, Kenneth J. ; Chinnaiyan, Arul M. ; Tomlins, Scott A.

Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at [...]

Menée sur 112 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un cancer de la prostate, cette étude de séquençage des exons identifie des mutations fréquentes du gène SPOP et suggère qu'elles définissent un nouveau sous-type moléculaire de ce cancer

Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer

Barbieri, Christopher E. ; Baca, Sylvan C. ; Lawrence, Michael S. ; Demichelis, Francesca ; Blattner, Mirjam ; Theurillat, Jean-Philippe ; White, Thomas A. ; Stojanov, Petar ; Van Allen, Eliezer ; Stransky, Nicolas ; Nickerson, Elizabeth ; Chae, Sung-Suk ; Boysen, Gunther ; Auclair, Daniel ; Onofrio, Robert C. ; Park, Kyung ; Kitabayashi, Naoki ; MacDonald, Theresa Y. ; Sheikh, Karen ; Vuong, Terry ; Guiducci, Candace ; Cibulskis, Kristian ; Sivachenko, Andrey ; Carter, Scott L. ; Saksena, Gordon ; Voet, Douglas ; Hussain, Wasay M. ; Ramos, Alex H. ; Winckler, Wendy ; Redman, Michelle C. ; Ardlie, Kristin ; Tewari, Ashutosh K. ; Mosquera, Juan Miguel ; Rupp, Niels ; Wild, Peter J. ; Moch, Holger ; Morrissey, Colm ; Nelson, Peter S. ; Kantoff, Philip W. ; Gabriel, Stacey B. ; Golub, Todd R. ; Meyerson, Matthew ; Lander, Eric S. ; Getz, Gad ; Rubin, Mark A. ; Garraway, Levi A.

Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate [...]

Menée sur 100 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude identifie des mutations "conductrices" dans plus de 40 gènes et met en évidence 73 combinaisons différentes de gènes mutés

The landscape of cancer genes and mutational processes in breast cancer

Stephens, Philip J. ; Tarpey, Patrick S. ; Davies, Helen ; Van Loo, Peter ; Greenman, Chris ; Wedge, David C. ; Zainal, Serena Nik ; Martin, Sancha ; Varela, Ignacio ; Bignell, Graham R. ; Yates, Lucy R. ; Papaemmanuil, Elli ; Beare, David ; Butler, Adam ; Cheverton, Angela ; Gamble, John ; Hinton, Jonathan ; Jia, Mingming ; Jayakumar, Alagu ; Jones, David ; Latimer, Calli ; Lau, King Wai ; McLaren, Stuart ; McBride, David J. ; Menzies, Andrew ; Mudie, Laura ; Raine, Keiran ; Rad, Roland ; Spencer Chapman, Michael ; Teague, Jon ; Easton, Douglas ; Langerod, Anita ; Osbreac, ; Lee, Ming Ta Michael ; Shen, Chen-Yang ; Tee, Benita Tan Kiat ; Huimin, Bernice Wong ; Broeks, Annegien ; Vargas, Ana Cristina ; Turashvili, Gulisa ; Martens, John ; Fatima, Aquila ; Miron, Penelope ; Chin, Suet-Feung ; Thomas, Gilles ; Boyault, Sandrine ; Mariani, Odette ; Lakhani, Sunil R. ; van de Vijver, Marc ; van /`t Veer, Laura ; Foekens, John ; Desmedt, Christine ; Sotiriou, Christos ; Tutt, Andrew ; Caldas, Carlos ; Reis-Filho, Jorge S. ; Aparicio, Samuel A. J. R. ; Salomon, Anne Vincent ; Borresen-Dale, Anne-Lise ; Richardson, Andrea ; Campbell, Peter J. ; Futreal, P. Andrew ; Stratton, Michael R.

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of [...]

Menée sur des lignées cellulaires et 360 échantillons tumoraux prélevés sur des patients atteints d'un cancer de l'estomac, cette étude met en évidence la surexpression de la protéine CRKL en association avec un sous-groupe de patients

The CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancer

Natsume, Hiroko ; Shinmura, Kazuya ; Tao, Hong ; Igarashi, Hisaki ; Suzuki, Masaya ; Nagura, Kiyoko ; Goto, Masanori ; Yamada, Hidetaka ; Maeda, Matsuyoshi ; Konno, Hrioyuki ; Nakamura, Satoki ; Sugimura, Haruhiko

BACKGROUND:Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. We searched for the possible amplification of other genes in gastric cancer. Methods and Results A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en interagissant avec p53, la protéine RASSF3 exerce une fonction de suppresseur de tumeurs

The RASSF3 Candidate Tumor Suppressor Induces Apoptosis and G1–S Cell-Cycle Arrest via p53

Kudo, Takumi ; Ikeda, Mitsunobu ; Nishikawa, Misa ; Yang, Zeyu ; Ohno, Kikuo ; Nakagawa, Kentaro ; Hata, Yutaka

RASSF3 is the smallest member of the RASSF family of proteins that function as tumor suppressors. Unlike other members of this important family, the mechanisms through which RASSF3 suppresses tumor formation remain unknown. Here, we show that RASSF3 expression induces p53-dependent apoptosis and its depletion attenuates DNA damage–induced apoptosis. We found that RASSF3-induced apoptosis depended upon p53 expression. Exogenous expression of RASSF3 induced G1–S arrest, which was also p53 [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel la kinase Aurora B régule l'expression du gène suppresseur de tumeurs p53

Aurora B kinase phosphorylates and instigates degradation of p53

Gully, Chris P. ; Velazquez-Torres, Guermarie ; Shin, Ji-Hyun ; Fuentes-Mattei, Enrique ; Wang, Edward ; Carlock, Colin ; Chen, Jian ; Rothenberg, Daniel ; Adams, Henry P. ; Choi, Hyun Ho ; Guma, Sergei ; Phan, Liem ; Chou, Ping-Chieh ; Su, Chun-Hui ; Zhang, Fanmao ; Chen, Jiun-Sheng ; Yang, Tsung-Ying ; Yeung, Sai-Ching J. ; Lee, Mong-Hong

Aurora B is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Aurora B is overexpressed in many types of human cancers, which has made it an attractive target for cancer therapies. Tumor suppressor p53 is a genome guardian and important negative regulator of the cell cycle. Whether Aurora B and p53 are coordinately regulated during the cell cycle is not known. We report that Aurora B directly [...]

Menée in vitro, à l'aide de xénogreffes et sur des échantillons tumoraux prélevés sur des patients atteints d'un mélanome ou d'un cancer du sein, cette étude met én évidence le rôle joué par la protéine de choc thermique HSP27 dans le phénomène de dormance tumorale

Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer

Straume, Oddbjørn ; Shimamura, Takeshi ; Lampa, Michael J. G. ; Carretero, Julian ; Øyan, Anne M. ; Jia, Di ; Borgman, Christa L. ; Soucheray, Margaret ; Downing, Sean R. ; Short, Sarah M. ; Kang, Soo-Young ; Wang, Souming ; Chen, Liang ; Collett, Karin ; Bachmann, Ingeborg ; Wong, Kwok-Kin ; Shapiro, Geoffrey I. ; Kalland, Karl Henning ; Folkman, Judah ; Watnick, Randolph S. ; Akslen, Lars A. ; Naumov, George N.

The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis, and reported that the angiogenic switch was preceded by a local increase in VEGF-A and basic fibroblast growth factor. In this breast cancer xenograft model (MDA-MB-436 cells), analysis of differentially expressed genes revealed that heat shock protein 27 (HSP27) was significantly up-regulated in [...]

Menée in vitro et in vivo, cette étude suggère que le micro-ARN 16 joue un rôle de suppresseur de tumeurs dans les cancers du sein induits par une hormone progestative

Downregulation of the tumor-suppressor miR-16 via progestin-mediated oncogenic signaling contributes to breast cancer development

Rivas, Martin ; Venturutti, Leandro ; Huang, Yi-Wen ; Schillaci, Roxana ; Huang, Tim ; Elizalde, Patricia

INTRODUCTION:Experimental and clinical evidence points to a critical role of progesterone and the nuclear progesterone receptor (PR) in controlling mammary gland tumorigenesis. However, the molecular mechanisms of progesterone action in breast cancer still remain elusive. On the other hand, micro RNAs (miRNAs) are short ribonucleic acids which have also been found to play a pivotal role in cancer pathogenesis. The role of miRNA in progestin-induced breast cancer is poorly explored. In this [...]

Cette étude met en évidence un mécanisme par lequel la formation de protrusions cellulaires analogues à des filopodes favorise le processus métastatique

The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions

Shibue, Tsukasa ; Brooks, Mary W. ; Inan, M. Fatih ; Reinhardt, Ferenc ; Weinberg, Robert A

Disseminated cancer cells that have extravasated into the tissue parenchyma must interact productively with its extracellular matrix (ECM) components in order to survive, proliferate and form macroscopic metastases. The biochemical and cell-biological mechanisms enabling this interaction remain poorly understood. We find that the formation of elongated, integrin β1-containing adhesion plaques by cancer cells that have extravasated into the lung parenchyma enables the proliferation of these [...]

Cet article passe en revue les travaux récents sur le rôle des cellules souches mésenchymateuses dans la progression tumorale et la résistance thérapeutique

The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression

Houthuijzen, J. M. ; Daenen, L. G. M. ; Roodhart, J. M. L. ; Voest, E. E.

It is becoming increasingly clear that the tumour microenvironment has a very important role in tumour progression and drug resistance. Many different cell types within the tumour stroma have an effect on tumour progression either in a positive or in a negative way. Mesenchymal stem cells (MSCs) are a distinct population of cells that have been linked with tumour growth. Mesenchymal stem cells can home to tumours where they modulate the immune system and facilitate tumour growth, angiogenesis [...]

Menée sur des lignées cellulaires, des modèles murins et des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel, en régulant l'expression des gènes DAPK et KLF4, les micro-ARNs 103 et 107 favorisent le processus métastatique

miR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4

Chen, Ruey-Hwa ; Chen, Hsin-Yi ; Lin, Yu-Min ; Chung, Hsiang-Ching ; Lang, Yaw-Dong ; Lin, Ching-Jung ; Huang, John ; Wang, Wei-Chi ; Lin, Feng-Mao ; Chen, Zhen ; Huang, Hsien-Da ; Shyy, John Y-J ; Liang, Jin-Tung

Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of microRNAs (miRNAs) to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in CRC patients. We demonstrated that miR-103/107 targeted the known metastasis suppressors DAPK and KLF4 in CRC cells, resulting in increased cell motility and cell-matrix [...]

A partir de travaux portant sur 909 échantillons, cette étude démontre la faisabilité d'une méthode de séquençage à faible taux de couverture pour améliorer la puissance des études d'association sur le génome entier

Extremely low-coverage sequencing and imputation increases power for genome-wide association studies

Pasaniuc, Bogdan ; Rohland, Nadin ; McLaren, Paul J. ; Garimella, Kiran ; Zaitlen, Noah ; Li, Heng ; Gupta, Namrata ; Neale, Benjamin M. ; Daly, Mark J. ; Sklar, Pamela ; Sullivan, Patrick F. ; Bergen, Sarah ; Moran, Jennifer L. ; Hultman, Christina M. ; Lichtenstein, Paul ; Magnusson, Patrik ; Purcell, Shaun M. ; Haas, David W. ; Liang, Liming ; Sunyaev, Shamil ; Patterson, Nick ; de Bakker, Paul I. W. ; Reich, David ; Price, Alkes L.

Genome-wide association studies (GWAS) have proven to be a powerful method to identify common genetic variants contributing to susceptibility to common diseases. Here, we show that extremely low-coverage sequencing (0.1–0.5×) captures almost as much of the common (>5%) and low-frequency (1–5%) variation across the genome as SNP arrays. As an empirical demonstration, we show that genome-wide SNP genotypes can be inferred at a mean r2 of 0.71 using off-target data (0.24× average coverage) in a [...]