Menée sur des échantillons tumoraux prélevés sur 27 patients atteints d'un carcinome hépatocellulaire, dont 25 étaient associés à une infection par un virus de l'hépatite B ou C, cette étude japonaise identifie la présence fréquente de mutations de gènes impliqués dans la régulation de la chromatine

Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

Fujimoto, Akihiro ; Totoki, Yasushi ; Abe, Tetsuo ; Boroevich, Keith A. ; Hosoda, Fumie ; Nguyen, Ha Hai ; Aoki, Masayuki ; Hosono, Naoya ; Kubo, Michiaki ; Miya, Fuyuki ; Arai, Yasuhito ; Takahashi, Hiroyuki ; Shirakihara, Takuya ; Nagasaki, Masao ; Shibuya, Tetsuo ; Nakano, Kaoru ; Watanabe-Makino, Kumiko ; Tanaka, Hiroko ; Nakamura, Hiromi ; Kusuda, Jun ; Ojima, Hidenori ; Shimada, Kazuaki ; Okusaka, Takuji ; Ueno, Masaki ; Shigekawa, Yoshinobu ; Kawakami, Yoshiiku ; Arihiro, Koji ; Ohdan, Hideki ; Gotoh, Kunihito ; Ishikawa, Osamu ; Ariizumi, Shun-ichi ; Yamamoto, Masakazu ; Yamada, Terumasa ; Chayama, Kazuaki ; Kosuge, Tomoo ; Yamaue, Hiroki ; Kamatani, Naoyuki ; Miyano, Satoru ; Nakagama, Hitoshi ; Nakamura, Yusuke ; Tsunoda, Tatsuhiko ; Shibata, Tatsuhiro ; Nakagawa, Hidewaki

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared [...]

Menée in vitro et in silico, cette étude identifie des délétions hémizygotes associées à l’optimisation des capacités de prolifération des cellules cancéreuses

Recurrent Hemizygous Deletions in Cancers May Optimize Proliferative Potential

Solimini, Nicole L. ; Xu, Qikai ; Mermel, Craig H. ; Liang, Anthony C. ; Schlabach, Michael R. ; Luo, Ji ; Burrows, Anna E. ; Anselmo, Anthony N. ; Bredemeyer, Andrea L. ; Li, Mamie Z. ; Beroukhim, Rameen ; Meyerson, Matthew ; Elledge, Stephen J.

Tumors exhibit numerous recurrent hemizygous focal deletions that contain no known tumor suppressors and are poorly understood. To investigate whether these regions contribute to tumorigenesis, we searched genetically for genes with cancer-relevant properties within these hemizygous deletions. We identified STOP and GO genes, which negatively and positively regulate proliferation, respectively. STOP genes include many known tumor suppressors, while GO genes are enriched for essential genes. [...]

Menée sur 161 cas de leucémie lymphocytaire chronique, cette étude identifie des loci sur les chromosomes 3q26 et 8q24 associés respectivement à une amplification des gènes PIK3CA et MYC

Integrative Genomic Analysis Implicates Gain of PIK3CA at 3q26 and MYC at 8q24 in Chronic Lymphocytic Leukemia

Brown, Jennifer R. ; Hanna, Megan ; Tesar, Bethany ; Werner, Lillian ; Pochet, Nathalie ; Asara, John M ; Wang, Yaoyu E ; Dal Cin, Paola ; Fernandes, Stacey ; Thompson, Christina ; MacConaill, Laura E. ; Wu, Catherine J ; Van de Peer, Yves ; Correll, Mick ; Regev, Aviv ; Neuberg, Donna ; Freedman, Arnold S

Purpose: The disease course of chronic lymphocytic leukemia (CLL) varies significantly within cytogenetic groups. We hypothesized that high resolution genomic analysis of CLL would identify additional recurrent abnormalities associated with short time to first therapy (TTFT). Experimental Design: We undertook high resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this dataset with gene expression profiles. Results: Copy [...]

Menée sur 291 échantillons prélevés sur 132 patients atteints d'un mélanome, cette étude analyse la distribution des mutations des gènes BRAF, NRAS et p16CDKN2A dans les tumeurs primitives et les métastases

BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients With Melanoma

Colombino, Maria ; Capone, Mariaelena ; Lissia, Amelia ; Cossu, Antonio ; Rubino, Corrado ; De Giorgi, Vincenzo ; Massi, Daniela ; Fonsatti, Ester ; Staibano, Stefania ; Nappi, Oscar ; Pagani, Elena ; Casula, Milena ; Manca, Antonella ; Sini, MariaCristina ; Franco, Renato ; Botti, Gerardo ; Caracò, Corrado ; Mozzillo, Nicola ; Ascierto, Paolo A. ; Palmieri, Giuseppe

Purpose The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues.Patients and Methods In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis [...]

Menée sur 25 échantillons tumoraux prélevés sur des patients atteints d'un mélanome métastatique, puis validée sur une cohorte indépendante de 107 cas de mélanome, cette étude de séquençage identifie la présence fréquente de mutations du gène PREX2

Melanoma genome sequencing reveals frequent PREX2 mutations

Berger, Michael F. ; Hodis, Eran ; Heffernan, Timothy P. ; Deribe, Yonathan Lissanu ; Lawrence, Michael S. ; Protopopov, Alexei ; Ivanova, Elena ; Watson, Ian R. ; Nickerson, Elizabeth ; Ghosh, Papia ; Zhang, Hailei ; Zeid, Rhamy ; Ren, Xiaojia ; Cibulskis, Kristian ; Sivachenko, Andrey Y. ; Wagle, Nikhil ; Sucker, Antje ; Sougnez, Carrie ; Onofrio, Robert ; Ambrogio, Lauren ; Auclair, Daniel ; Fennell, Timothy ; Carter, Scott L. ; Drier, Yotam ; Stojanov, Petar ; Singer, Meredith A. ; Voet, Douglas ; Jing, Rui ; Saksena, Gordon ; Barretina, Jordi ; Ramos, Alex H. ; Pugh, Trevor J. ; Stransky, Nicolas ; Parkin, Melissa ; Winckler, Wendy ; Mahan, Scott ; Ardlie, Kristin ; Baldwin, Jennifer ; Wargo, Jennifer ; Schadendorf, Dirk ; Meyerson, Matthew ; Gabriel, Stacey B. ; Golub, Todd R. ; Wagner, Stephan N. ; Lander, Eric S. ; Getz, Gad ; Chin, Lynda ; Garraway, Levi A.

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those [...]

Menée sur 59 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un adénocarcinome pulmonaire, cette étude identifie, à l'échelle du génome entier, des anomalies de méthylation de l'ADN

Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression

Selamat, Suhaida A. ; Chung, Brian S. ; Girard, Luc ; Zhang, Wei ; Zhang, Ying ; Campan, Mihaela ; Siegmund, Kimberly D. ; Koss, Michael N. ; Hagen, Jeffrey A. ; Lam, Wan L. ; Lam, Stephen ; Gazdar, Adi F. ; Laird-Offringa, Ite A.

Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We [...]

Cet article passe en revue les travaux récents sur les contraintes spatiales de la régulation des récepteurs à activité tyrosine kinase dans le développement d'un cancer

Spatial regulation of receptor tyrosine kinases in development and cancer

Casaletto, Jessica B. ; McClatchey, Andrea I.

During development and tissue homeostasis, patterns of cellular organization, proliferation and movement are highly choreographed. Receptor tyrosine kinases (RTKs) have a crucial role in establishing these patterns. Individual cells and tissues exhibit tight spatial control of the RTKs that they express, enabling tissue morphogenesis and function, while preventing unwarranted cell division and migration that can contribute to tumorigenesis. Indeed, RTKs are deregulated in most human cancers and [...]

Menée in vitro et à l'aide de xénogreffes, cette étude identifie des voies de signalisation en interaction de "létalité synthétique" avec l'oncogène MYC

Functional genomics identifies therapeutic targets for MYC-driven cancer

Toyoshima, Masafumi ; Howie, Heather L. ; Imakura, Maki ; Walsh, Ryan M. ; Annis, James E. ; Chang, Aaron N. ; Frazier, Jason ; Chau, B. Nelson ; Loboda, Andrey ; Linsley, Peter S. ; Cleary, Michele A. ; Park, Julie R. ; Grandori, Carla

MYC oncogene family members are broadly implicated in human cancers, yet are considered “undruggable” as they encode transcription factors. MYC also carries out essential functions in proliferative tissues, suggesting that its inhibition could cause severe side effects. We elected to identify synthetic lethal interactions with c-MYC overexpression (MYC-SL) in a collection of ∼3,300 druggable genes, using high-throughput siRNA screening. Of 49 genes selected for follow-up, 48 were confirmed by [...]

Cet article passe en revue les travaux récents sur le rôle de nouvelles classes d'ARNs non codants dans le développement d'un cancer

Novel classes of non-coding RNAs and cancer

Sana, Jiri ; Faltejskova, Petra ; Svoboda, Marek ; Slaby, Ondrej

For the many years, the central dogma of molecular biology has been that RNA functions mainly as an informational intermediate between a DNA sequence and its encoded protein. But one of the great surprises of modern biology was the discovery that protein-coding genes represent only <2% of the total genome sequence, and consequently the fact that at least 90% of the human genome is actively transcribed. Thus, the human transcriptome was found to be more complex than a collection of [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par des mutations des gènes Rb, p53 et BRCA1/2 dans la formation de tumeurs séreuses de l'épithélium ovarien

Perturbation of Rb, p53 and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer

Szabova, Ludmila ; Yin, Chaoying ; Bupp, Sujata ; Guerin, Theresa M ; Schlomer, Jerome J ; Householder, Deborah B ; Baran, Maureen L ; Yi, Ming ; Song, Yurong ; Sun, Wenping ; McDunn, Jonathan E. ; Martin, Philip L ; Van Dyke, Terry ; Difilippantonio, Simone

The majority of human high grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and [...]

Menée in vitro, cette étude montre que, dans les cellules de cancer de la prostate, la surexpression d'un oncogène, le facteur de transcription ERG, est associée à des modifications cohérentes de l'organisation de la chromatine

Oncogene-mediated alterations in chromatin conformation

Rickman, David S. ; Soong, T. David ; Moss, Benjamin ; Mosquera, Juan Miguel ; Dlabal, Jan ; Terry, Stéphane ; MacDonald, Theresa Y. ; Tripodi, Joseph ; Bunting, Karen ; Najfeld, Vesna ; Demichelis, Francesca ; Melnick, Ari M. ; Elemento, Olivier ; Rubin, Mark A.

Emerging evidence suggests that chromatin adopts a nonrandom 3D topology and that the organization of genes into structural hubs and domains affects their transcriptional status. How chromatin conformation changes in diseases such as cancer is poorly understood. Moreover, how oncogenic transcription factors, which bind to thousands of sites across the genome, influence gene regulation by globally altering the topology of chromatin requires further investigation. To address these questions, we [...]

Menée in vitro, cette étude montre que le récepteur EphA2 est une porte d'entrée pour l'herpèvirus associé au sarcome de Kaposi dans les cellules de l'hôte

The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma-associated herpesvirus

Hahn, Alexander S. ; Kaufmann, Johanna K. ; Wies, Effi ; Naschberger, Elisabeth ; Panteleev-Ivlev, Julia ; Schmidt, Katharina ; Holzer, Angela ; Schmidt, Martin ; Chen, Jin ; Konig, Simone ; Ensser, Armin ; Myoung, Jinjong ; Brockmeyer, Norbert H. ; Sturzl, Michael ; Fleckenstein, Bernhard ; Neipel, Frank

Kaposi's sarcoma–associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, a highly vascularized tumor originating from lymphatic endothelial cells, and of at least two different B cell malignancies. A dimeric complex formed by the envelope glycoproteins H and L (gH-gL) is required for entry of herpesviruses into host cells. We show that the ephrin receptor tyrosine kinase A2 (EphA2) is a cellular receptor for KSHV gH-gL. EphA2 co-precipitated with both gH-gL and KSHV virions. [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'activation de MET dans les cellules souches de glioblastome

MET Signaling Regulates Glioblastoma Stem Cells

Joo, Kyeung Min ; Jin, Juyoun ; Kim, Eunhee ; Kim, Kang Ho ; Kim, Yonghyun ; Kang, Bong Gu ; Kang, Youn-Jung ; Lathia, Justin D ; Cheng, Kwang Ho ; Song, Paul ; Kim, Hyunggee ; Seol, Ho Jun ; Kong, Doo-Sik ; Lee, Jung-Il ; Rich, Jeremy N ; Lee, Jeongwu ; Nam, Do-Hyun

Glioblastomas (GBMs) contain highly tumorigenic, self-renewing populations of stem/initiating cells (GSCs) that contribute to tumor propagation and treatment resistance. However, our knowledge of the specific signaling pathways that regulate GSCs is limited. The MET tyrosine kinase is known to stimulate the survival, proliferation, and invasion of various cancers including GBM. Here, we identified a distinct fraction of cells expressing a high level of MET in human primary GBM specimens that [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude suggère que la protéine YAP1, impliquée dans la voie de signalisation Hippo, joue un rôle d'oncogène dans les méningiomes

Yes-Associated Protein 1 Is Activated and Functions as an Oncogene in Meningiomas

Baia, Gilson S ; Caballero, Otavia L ; Orr, Brent A ; Lal, Anita ; Ho, Janelle S.Y. ; Cowdrey, Cynthia ; Tihan, Tarik ; Mawrin, Christian ; Riggins, Gregory J

The Hippo signaling pathway is functionally conserved in Drosophila melanogaster and mammals and its proposed function is to control tissue homeostasis by regulating cell proliferation and apoptosis. The core components are comprised of a kinase cascade that culminates with the phosphorylation and inhibition of Yes-associated protein 1 (YAP1). Phospho-YAP1 is retained in the cytoplasm. In the absence of Hippo signaling, YAP1 translocates to the nucleus, associates with co-activators TEAD1-4 and [...]

Cet article passe en revue les travaux récents sur le rôle d'une transition épithélio-mésenchymateuse induite par la cytokine TGF-β dans les processus inflammatoire et métastatique

TGF-β-induced epithelial-mesenchymal transition: A link between cancer and inflammation

Fuxe, Jonas ; Karlsson, Mikael C. I.

Metastatic spread of tumor cells to vital organs is the major cause of death in cancer. Accumulating data support an important role of infiltrating immune cells in promoting carcinoma progression into metastatic disease. Tumor-infiltrating immune cells produce and secrete cytokines, growth factors and proteases that re-activate latent developmental processes including epithelial-mesenchymal transition (EMT). EMT provides tumor cells with invasive, migratory and stem cell properties allowing [...]

Cet article propose un nouveau modèle intégrant un jeu de forces mécaniques pour rendre compte du processus métastatique

A New Paradigm for Mechanobiological Mechanisms in Tumor Metastasis

Torzilli, Peter A. ; Bourne, Jonathan W. ; Cigler, Tessa ; Vincent, C. Theresa

Tumor metastases and epithelial to mesenchymal transition (EMT) involve tumor cell invasion and migration through the dense collagen-rich extracellular matrix surrounding the tumor. Little is known about the mechanobiological mechanisms involved in this process, nor the role of the mechanical forces generated by the cells in their effort to invade and migrate through the stroma. In this paper we propose a new fundamental mechanobiological mechanism involved in cancer growth and metastasis, [...]

Menée à l'aide d'un modèle murin et sur des échantillons tumoraux prélevés sur des patients atteints d'un mélanome, cette étude met en évidence un mécanisme par lequel des exosomes dérivés des tumeurs favorisent le processus métastatique

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

Peinado, Hector ; Aleckovic, Masa ; Lavotshkin, Simon ; Matei, Irina ; Costa-Silva, Bruno ; Moreno-Bueno, Gema ; Hergueta-Redondo, Marta ; Williams, Caitlin ; Garcia-Santos, Guillermo ; Ghajar, Cyrus M. ; Nitadori-Hoshino, Ayuko ; Hoffman, Caitlin ; Badal, Karen ; Garcia, Benjamin A. ; Callahan, Margaret K. ; Yuan, Jianda ; Martins, Vilma R. ; Skog, Johan ; Kaplan, Rosandra N. ; Brady, Mary S. ; Wolchok, Jedd D. ; Chapman, Paul B. ; Kang, Yibin ; Bromberg, Jacqueline ; Lyden, David

Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow [...]

Cet article analyse le rôle joué par la transition épithélio-mésenchymateuse dans la formation de cellules souches cancéreuses

EMT in breast cancer stem cell generation

Ansieau, Stéphane

The concept of cancer stem cells (CSCs) has been proposed to explain the ability of single disseminated cancer cells to reconstitute tumours with heterogeneity similar to that of the primary tumour they arise from. Although this concept is now commonly accepted, the origin of these CSCs remains a source of debate. First proposed to arise through stem/progenitor cell transformation, CSCs might also or alternatively arise from differentiated cancer cells through epithelial to mesenchymal [...]