A l'aide d'échantillons sanguins prélevés sur 14 patients atteints d'une leucémie agressive à cellules NK, cette étude identifie un ensemble d'anomalies génomiques suggèrant l'intérêt d'un traitement à l'aide d'inhibiteurs de JAK et BCL2

Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

Dufva, Olli ; Kankainen, Matti ; Kelkka, Tiina ; Sekiguchi, Nodoka ; Awad, Shady Adnan ; Eldfors, Samuli ; Yadav, Bhagwan ; Kuusanmäki, Heikki ; Malani, Disha ; Andersson, Emma I. ; Pietarinen, Paavo ; Saikko, Leena ; Kovanen, Panu E. ; Ojala, Teija ; Lee, Dean A. ; Loughran, Thomas P. ; Nakazawa, Hideyuki ; Suzumiya, Junji ; Suzuki, Ritsuro ; Ko, Young Hyeh ; Kim, Won Seog ; Chuang, Shih-Sung ; Aittokallio, Tero ; Chan, Wing C. ; Ohshima, Koichi ; Ishida, Fumihiro ; Mustjoki, Satu

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT [...]

Cet article passe en revue les travaux récents sur les fréquentes anomalies génomiques observées dans les mélanomes et analyse leur pertinence thérapeutique

Melanoma: What do all the mutations mean?

Elizabeth J. Davis ; Douglas B. Johnson ; Jeffrey A. Sosman ; Sunandana Chandra

Melanoma is one of the most highly mutated malignancies, largely as a function of its generation through ultraviolet light and other mutational processes. The wide array of mutations in both “driver” and “passenger” genes can present a confusing array of data for practitioners, particularly within the context of the recent revolutions in targeted and immune therapy. Although mutations in BRAF V600 clearly confer sensitivity to BRAF and mitogen‐activated protein kinase kinase (MEK) inhibitors, [...]

A partir d'échantillons de tumeurs primitives et de métastases prélevés sur 112 patients atteints d'un cancer de la prostate, ainsi qu'à l'aide de données complémentaires portant sur 930 patients au total, cette étude identifie de nouveaux gènes qui, affectés par des mutations codantes ou non codantes, sont impliqués dans la cancérogenèse

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Wedge, David C. ; Gundem, Gunes ; Mitchell, Thomas ; Woodcock, Dan J. ; Martincorena, Inigo ; Ghori, Mohammed ; Zamora, Jorge ; Butler, Adam ; Whitaker, Hayley ; Kote-Jarai, Zsofia ; Alexandrov, Ludmil B. ; Van Loo, Peter ; Massie, Charlie E. ; Dentro, Stefan ; Warren, Anne Y. ; Verrill, Clare ; Berney, Dan M. ; Dennis, Nening ; Merson, Sue ; Hawkins, Steve ; Howat, William ; Lu, Yong-Jie ; Lambert, Adam ; Kay, Jonathan ; Kremeyer, Barbara ; Karaszi, Katalin ; Luxton, Hayley ; Camacho, Niedzica ; Marsden, Luke ; Edwards, Sandra ; Matthews, Lucy ; Bo, Valeria ; Leongamornlert, Daniel ; McLaren, Stuart ; Ng, Anthony ; Yu, Yongwei ; Zhang, Hongwei ; Dadaev, Tokhir ; Thomas, Sarah ; Easton, Douglas F. ; Ahmed, Mahbubl ; Bancroft, Elizabeth ; Fisher, Cyril ; Livni, Naomi ; Nicol, David ; Tavare, Simon ; Gill, Pelvender ; Greenman, Christopher ; Khoo, Vincent ; Van As, Nicholas ; Kumar, Pardeep ; Ogden, Christopher ; Cahill, Declan ; Thompson, Alan ; Mayer, Erik ; Rowe, Edward ; Dudderidge, Tim ; Gnanapragasam, Vincent ; Shah, Nimish C. ; Raine, Keiran ; Jones, David ; Menzies, Andrew ; Stebbings, Lucy ; Teague, Jon ; Hazell, Steven ; Corbishley, Cathy ; de Bono, Johann ; Attard, Gerhardt ; Isaacs, William ; Visakorpi, Tapio ; Fraser, Michael ; Boutros, Paul C. ; Bristow, Robert G. ; Workman, Paul ; Sander, Chris ; Hamdy, Freddie C. ; Futreal, Andrew ; McDermott, Ultan ; Al-Lazikani, Bissan ; Lynch, Andrew G. ; Bova, G. Steven ; Foster, Christopher S. ; Brewer, Daniel S. ; Neal, David E. ; Cooper, Colin S. ; Eeles, Rosalind A.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding [...]

Menée à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, puis à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence le rôle joué par des éléments d'ADN non chromosomiques dans l'accroissement de l'hétérogénéité génomique d'une tumeur au cours de son évolution

Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma

deCarvalho, Ana C. ; Kim, Hoon ; Poisson, Laila M. ; Winn, Mary E. ; Mueller, Claudius ; Cherba, David ; Koeman, Julie ; Seth, Sahil ; Protopopov, Alexei ; Felicella, Michelle ; Zheng, Siyuan ; Multani, Asha ; Jiang, Yongying ; Zhang, Jianhua ; Nam, Do-Hyun ; Petricoin, Emanuel F. ; Chin, Lynda ; Mikkelsen, Tom ; Verhaak, Roel G. W.

To understand how genomic heterogeneity of glioblastoma (GBM) contributes to poor therapy response, we performed DNA and RNA sequencing on GBM samples and the neurospheres and orthotopic xenograft models derived from them. We used the resulting dataset to show that somatic driver alterations including single-nucleotide variants, focal DNA alterations and oncogene amplification on extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, [...]

Menée in vitro et in vivo sur des modèles de cancer de l'estomac, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de MYC, les protéines YAP et TAZ favorisent le développement d'une tumeur

YAP/TAZ initiates gastric tumorigenesis via upregulation of MYC

Choi, Wonyoung ; Kim, Jeongsik ; Park, Jaeoh ; Lee, Da-Hye ; Hwang, Daehee ; Kim, Jeong-Hwan ; Ashktorab, Hassan ; Smoot, Duane T. ; Kim, Seon-Young ; Choi, Chan ; Koh, Gou Young ; Lim, Dae-Sik

YAP and TAZ play oncogenic roles in various organs, but the role of YAP/TAZ in gastric cancer remains unclear. Here we show that YAP/TAZ activation initiates gastric tumorigenesis in vivo and verify its significance in human gastric cancer. In mice, YAP/TAZ activation in the pyloric stem cell led to step-wise tumorigenesis. RNA sequencing identified MYC as a decisive target of YAP, which controls MYC at transcriptional and post-transcriptional levels. These mechanisms tightly regulated MYC in [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels la protéine MET exerce une fonction oncogénique, puis évalue les perspectives thérapeutiques offertes par ces travaux

Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy

Comoglio, Paolo M. ; Trusolino, Livio ; Boccaccio, Carla

The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered (‘oncogene addiction’) and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions (‘oncogene expedience’). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels, en sécrétant diverses molécules (cytokines, chimiokines, facteurs de croissance), les cellules sénescentes favorisent la tumorigenèse

Paracrine roles of cellular senescence in promoting tumourigenesis

Gonzalez-Meljem, Jose Mario ; Apps, John Richard ; Fraser, Helen Christina ; Martinez-Barbera, Juan Pedro

Senescent cells activate genetic programmes that irreversibly inhibit cellular proliferation, but also endow these cells with distinctive metabolic and signalling phenotypes. Although senescence has historically been considered a protective mechanism against tumourigenesis, the activities of senescent cells are increasingly being associated with age-related diseases, including cancer. An important feature of senescent cells is the secretion of a vast array of pro-inflammatory cytokines, [...]

Menée sur 3 321 cellules cancéreuses issues d'échantillons tumoraux prélevés chez 6 patients atteints d'un gliome présentant des mutations H3K27M, cette étude identifie la présence majoritaire de cellules analogues à des précurseurs d'oligodendrocyte par rapport aux cellules malignes plus différenciées

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq

Filbin, Mariella G. ; Tirosh, Itay ; Hovestadt, Volker ; Shaw, McKenzie L. ; Escalante, Leah E. ; Mathewson, Nathan D. ; Neftel, Cyril ; Frank, Nelli ; Pelton, Kristine ; Hebert, Christine M. ; Haberler, Christine ; Yizhak, Keren ; Gojo, Johannes ; Egervari, Kristof ; Mount, Christopher ; van Galen, Peter ; Bonal, Dennis M. ; Nguyen, Quang-De ; Beck, Alexander ; Sinai, Claire ; Czech, Thomas ; Dorfer, Christian ; Goumnerova, Liliana ; Lavarino, Cinzia ; Carcaboso, Angel M. ; Mora, Jaume ; Mylvaganam, Ravindra ; Luo, Christina C. ; Peyrl, Andreas ; Popović, Mara ; Azizi, Amedeo ; Batchelor, Tracy T. ; Frosch, Matthew P. ; Martinez-Lage, Maria ; Kieran, Mark W. ; Bandopadhayay, Pratiti ; Beroukhim, Rameen ; Fritsch, Gerhard ; Getz, Gad ; Rozenblatt-Rosen, Orit ; Wucherpfennig, Kai W. ; Louis, David N. ; Monje, Michelle ; Slavc, Irene ; Ligon, Keith L. ; Golub, Todd R. ; Regev, Aviv ; Bernstein, Bradley E. ; Suvà, Mario L.

Diffuse midline gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) are an aggressive type of childhood cancer with few options for treatment. Filbin et al. used a single-cell sequencing approach to study the oncogenic programs, genetics, and cellular hierarchies of H3K27M-glioma. Tumors were mainly composed of cells resembling oligodendrocyte precursor cells, whereas differentiated malignant cells were a smaller fraction. In comparison with other gliomas, these cancers had [...]

Menée in vitro et in vivo sur des modèles de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels, en interaction avec le récepteur des androgènes, la protéine COBLL1 favorise la prolifération et la migration des cellules cancéreuses, ainsi que la progression d'une tumeur vers la résistance à la castration

COBLL1 modulates cell morphology and facilitates androgen receptor genomic binding in advanced prostate cancer

Takayama, Ken-ichi ; Suzuki, Takashi ; Fujimura, Tetsuya ; Takahashi, Satoru ; Inoue, Satoshi

Activated androgen receptor signaling is a key driver to circumvent androgen-deprivation therapy in advanced prostate cancer. Cordon-bleu (COBL) has been identified as a specific player in morphogenesis by regulating actin networks in neurons. Here, we identify another COBL protein, COBL-like 1 (COBLL1), as an important factor that contributes to prostate cancer progression by stimulating androgen receptor signaling and modulating cell morphology. We show that COBLL1 is regulated by androgen [...]

Menée in vivo et in vitro sur des modèles de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, en régulant la polarisation des macrophages, la protéine MK2 favorise la tumorigenèse et l'angiogenèse tumorale

MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis

Suarez-Lopez, Lucia ; Sriram, Ganapathy ; Kong, Yi Wen ; Morandell, Sandra ; Merrick, Karl A. ; Hernandez, Yuliana ; Haigis, Kevin M. ; Yaffe, Michael B.

Colon cancer is the third most common cancer type and the second leading cause of cancer-related death. Chronic inflammation is a major contributor to colon cancer development and progression, but the molecular details of how inflammation contributes to colon cancer remain unclear. The p38MAPK/MAPKAP Kinase 2 (MK2) pathway is a central mediator of cell stress and inflammation. Here, we examine the importance of this pathway in an inflammation-driven model of colon cancer using whole-body and [...]

A partir de données issues du projet "The Cancer Genome Atlas" et portant sur 9 174 tumeurs (29 types de cancer), cette étude analyse le profil des cellules immunitaires infiltrant les tumeurs en fonction des caractérisques génomiques de ces dernières

A pan-cancer landscape of interactions between solid tumors and infiltrating immune cell populations

Tamborero, David ; Rubio-Perez, Carlota ; Muiños, Ferran ; Sabarinathan, Radhakrishnan ; Piulats, Josep Maria ; Muntasell, Aura ; Dienstmann, Rodrigo ; Lopez-Bigas, Nuria ; Gonzalez-Perez, Abel

Purpose: Throughout their development tumors are challenged by the immune system and they acquire features to evade its surveillance. A systematic view of these traits which sheds light on how tumors respond to immunotherapies is still lacking. Experimental Design: Here, we computed the relative abundance of an array of immune cell populations to measure the immune infiltration pattern of 9,174 tumors of 29 solid cancers. We then clustered tumors with similar infiltration pattern to define [...]

A partir d'échantillons tumoraux prélevés sur 293 patients atteints d'un cancer localisé de la prostate, cette étude analyse la diversification des populations clonales des tumeurs en lien avec les données cliniques

The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression

Espiritu, Shadrielle Melijah G. ; Liu, Lydia Y. ; Rubanova, Yulia ; Bhandari, Vinayak ; Holgersen, Erle M. ; Szyca, Lesia M. ; Fox, Natalie S. ; Chua, Melvin L. K. ; Yamaguchi, Takafumi N. ; Heisler, Lawrence E. ; Livingstone, Julie ; Wintersinger, Jeff ; Yousif, Fouad ; Lalonde, Emilie ; Rouette, Alexandre ; Salcedo, Adriana ; Houlahan, Kathleen E. ; Li, Constance H. ; Huang, Vincent ; Fraser, Michael ; van der Kwast, Theodorus ; Morris, Quaid D. ; Bristow, Robert G. ; Boutros, Paul C.

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal [...]