Cet article passe en revue les travaux récents sur les mécanismes induisant des réarrangements chromosomiques dans le génome des cellules cancéreuses

Deciphering the Code of the Cancer Genome: Mechanisms of Chromosome Rearrangement

Willis, Nicholas A. ; Rass, Emilie ; Scully, Ralph

Chromosome rearrangement plays a causal role in tumorigenesis by contributing to the inactivation of tumor-suppressor genes, the dysregulated expression or amplification of oncogenes, and to the generation of novel gene fusions. Chromosome breaks are important intermediates in this process. How, when, and where these breaks arise and the specific mechanisms engaged in their repair strongly influence the resulting patterns of chromosome rearrangement. We review recent progress in understanding [...]

A partir de données issues du projet "The Cancer Genome Atlas" portant sur plus de 10 000 échantillons tumoraux (21 types de cancer), cette étude analyse le niveau de "pureté" des échantillons, c'est-à-dire la proportion de cellules cancéreuses et de cellules du micro-environnement tumoral qu'ils contiennent

Systematic pan-cancer analysis of tumour purity

Aran, Dvir ; Sirota, Marina ; Butte, Atul J.

The tumour microenvironment is the non-cancerous cells present in and around a tumour, including mainly immune cells, but also fibroblasts and cells that comprise supporting blood vessels. These non-cancerous components of the tumour may play an important role in cancer biology. They also have a strong influence on the genomic analysis of tumour samples, and may alter the biological interpretation of results. Here we present a systematic analysis using different measurement modalities of tumour [...]

Menée sur 30 patients atteints d'une leucémie lymphocytaire chronique, cette étude suggère que des mutations induisant une activité de la cytidine désaminase surviennent de façon précoce dans l'évolution de la maladie

Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution

Kasar, S. ; Kim, J. ; Improgo, R. ; Tiao, G. ; Polak, P. ; Haradhvala, N. ; Lawrence, M. S. ; Kiezun, A. ; Fernandes, S. M. ; Bahl, S. ; Sougnez, C. ; Gabriel, S. ; Lander, E. S. ; Kim, H. T. ; Getz, G. ; Brown, J. R.

Patients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To better understand their genomic landscape, here we perform whole-genome sequencing on a cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and unmutated IGHV. The most commonly mutated gene in our [...]

A partir d'échantillons tumoraux prélevés sur 138 patients atteints d'un lymphome diffus à grandes cellules B récidivant ou réfractaire, cette étude identifie un ensemble de gènes dont les mutations sont associées à l'apparition d'une résistance thérapeutique

Genetic landscapes of relapsed and refractory diffuse large B cell lymphomas

Morin, Ryan D. ; Assouline, Sarit E. ; Alcaide, Miguel ; Mohajeri, Arezoo ; Johnston, Rebecca L ; Chong, Lauren ; Grewal, Jasleen ; Yu, Stephen ; Fornika, Daniel ; Bushell, Kevin ; Holm Nielsen, Torsten ; Petrogiannis-Haliotis, Tina ; Crump, Michael ; Tosikyan, Axel ; Grande, Bruno M ; Macdonald, David ; Rousseau, Caroline ; Bayat, Maryam ; Sesques, Pierre ; Froment, Remi ; Albuquerque, Marco ; Monczak, Yuri ; Klein-oros, Kathleen ; Greenwood, Celia ; Riazalhosseini, Yasser ; Arseneault, Madeleine ; Camlioglu, Errol ; Constantin, André Marc ; Pan-Hammarström, Qiang ; Peng, Rou-Jun ; Mann, Koren K. ; Johnson, Nathalie A.

Purpose: Relapsed or refractory diffuse large B cell lymphoma (rrDLBCL) is fatal in 90% of patients and yet little is known about its biology. Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately [...]

A partir d'échantillons tumoraux prélevés sur 47 patients atteints d'un adénocarcinome canalaire du pancréas, cette étude évalue l'hétérogénéité intratumorale des mutations du gène KRAS

Intratumor Heterogeneity of KRAS Mutation Status in Pancreatic Ductal Adenocarcinoma Is Associated With Smaller Lesions

Nagawkar, Sima S. ; Abu-Funni, Samah ; Simon, Einav ; Bick, Tova ; Prinz, Elad ; Sabo, Edmond ; Ben-Izhak, Ofer ; Hershkovitz, Dov

Objectives: Recent studies have demonstrated intratumor heterogeneity (ITH) for genetic mutations in various tumors and suggest that ITH might have significant clinical impact. Because KRAS is the most commonly mutated oncogene in pancreatic ductal adenocarcinoma and has an important role in pancreatic carcinogenesis, the purpose of this study was to evaluate ITH for KRAS gene mutation and its clinical significance. Methods: Deep sequencing of 47 pancreatic ductal adenocarcinoma cases was used [...]

Menée sur 123 échantillons prélevés sur des patients atteints d'un ostéosarcome, cette étude identifie des mutations dans des voies de signalisation qui, en favorisant une instabilité chromosomique, confèrent aux tumeurs des caractéristiques analogues aux tumeurs présentant un déficit en BRCA1/2

Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency

Kovac, Michal ; Blattmann, Claudia ; Ribi, Sebastian ; Smida, Jan ; Mueller, Nikola S. ; Engert, Florian ; Castro-Giner, Francesc ; Weischenfeldt, Joachim ; Kovacova, Monika ; Krieg, Andreas ; Andreou, Dimosthenis ; Tunn, Per-Ulf ; Durr, Hans Roland ; Rechl, Hans ; Schaser, Klaus-Dieter ; Melcher, Ingo ; Burdach, Stefan ; Kulozik, Andreas ; Specht, Katja ; Heinimann, Karl ; Fulda, Simone ; Bielack, Stefan ; Jundt, Gernot ; Tomlinson, Ian ; Korbel, Jan O. ; Nathrath, Michaela ; Baumhoer, Daniel

Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of [...]

A partir d'échantillons tumoraux prélevés à deux étapes de la maladie sur des patients atteints d'un gliome présentant un gène IDH1 muté, cette étude met en évidence plusieurs voies de signalisation alimentant la progression de la tumeur

Integrated genomic characterization of IDH1-mutant glioma malignant progression

Bai, Hanwen ; Harmanci, Akdes Serin ; Erson-Omay, E. Zeynep ; Li, Jie ; Coskun, Suleyman ; Simon, Matthias ; Krischek, Boris ; Özduman, Koray ; Omay, S. Bulent ; Sorensen, Eric A. ; Turcan, Sevin ; Bakirciglu, Mehmet ; Carrión-Grant, Geneive ; Murray, Phillip B. ; Clark, Victoria E. ; Ercan-Sencicek, A. Gulhan ; Knight, James ; Sencar, Leman ; Altinok, Selin ; Kaulen, Leon D. ; Gulez, Burcu ; Timmer, Marco ; Schramm, Johannes ; Mishra-Gorur, Ketu ; Henegariu, Octavian ; Moliterno, Jennifer ; Louvi, Angeliki ; Chan, Timothy A. ; Tannheimer, Stacey L. ; Pamir, M. Necmettin ; Vortmeyer, Alexander O. ; Bilgüvar, Kaya ; Yasuno, Katsuhito ; Günel, Murat

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA [...]

Menée in vitro et in vivo sur des modèles de cancer colorectal, cette étude met en évidence des mécanismes par lesquels la kinase MLK4 exerce une fonction de suppresseur de tumeurs

Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis

Marusiak, Anna A ; Stephenson, Natalie L ; Baik, Hayeon ; Trotter, Eleanor W ; Li, Yaoyong ; Blyth, Karen ; Mason, Susan ; Chapman, Phil ; Puto, Lorena A ; Read, Jon A ; Brassington, Claire ; Pollard, Hannah K ; Phillips, Chris ; Green, Isabelle ; Overman, Ross ; Collier, Matthew ; Testoni, Ewelina ; Miller, Crispin ; Hunter, Tony ; Sansom, Owen J. ; Brognard, John

MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers including frequently in colorectal cancer, where their function and pathobiological importance has been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can [...]

Cet article passe en revue les travaux récents sur les caractéristiques et les fonctions de divers niches anatomiques du cerveau à partir desquelles se développe une tumeur de glioblastome

Glioblastoma: Defining Tumor Niches

Hambardzumyan, Dolores ; Bergers, Gabriele

Glioblastomas (glioblastoma multiforme, GBM) are one of the most recalcitrant brain tumors because of their aggressive invasive growth and resistance to therapy. They are highly heterogeneous malignancies at both the molecular and histological levels. Specific histological hallmarks including pseudopalisading necrosis and microvascular proliferation distinguish GBM from lower-grade gliomas, and make GBM one of the most hypoxic as well as angiogenic tumors. These microanatomical compartments [...]

Menée à l'aide de modèles murins de gliomes, cette étude met en évidence des mécanismes suggérant que la signalisation Notch exerce une fonction de suppresseur de tumeurs

A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes

Giachino, Claudio ; Boulay, Jean-Louis ; Ivanek, Robert ; Alvarado, Alvaro ; Tostado, Cristobal ; Lugert, Sebastian ; Tchorz, Jan ; Coban, Mustafa ; Mariani, Luigi ; Bettler, Bernhard ; Lathia, Justin ; Frank, Stephan ; Pfister, Stefan ; Kool, Marcel ; Taylor, Verdon

In the brain, Notch signaling maintains normal neural stem cells, but also brain cancer stem cells, indicating an oncogenic role. Here, we identify an unexpected tumor suppressor function for Notch in forebrain tumor subtypes. Genetic inactivation of RBP-J

Menée à l'aide de modèles murins de mélanome, cette étude met en évidence des mécanismes par lesquels, en réprimant l'expression du gène codant la fucokinase, le facteur de transcription ATF2 favorise le processus métastatique

The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation

Lau, Eric ; Feng, Yongmei ; Claps, Giuseppina ; Fukuda, Michiko N. ; Perlina, Ally ; Donn, Dylan ; Jilaveanu, Lucia ; Kluger, Harriet ; Freeze, Hudson H. ; Ronai, Ze’ev A.

Metastatic melanoma is particularly challenging to treat. Lau et al. found that activation of the transcription factor ATF2 by the kinase PKCε, which was more prevalent in advanced-stage melanomas than in primary melanocytes or early-stage tumors, promoted the metastatic behavior of melanoma cells in culture and in mice. ATF2 repressed the expression of the gene encoding fucokinase (FUK), an enzyme that promotes global protein fucosylation. Supplementing drinking water with dietary fucose [...]

Menée in vitro et in vivo, cette étude française met en évidence des mécanismes par lesquels la perte d'expression du gène EZH2 favorise la progression d'un cancer du sein

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

Wassef, Michel ; Rodilla, Veronica ; Teissandier, Aurélie ; Zeitouni, Bruno ; Gruel, Nadege ; Sadacca, Benjamin ; Irondelle, Marie ; Charruel, Margaux ; Ducos, Bertrand ; Michaud, Audrey ; Caron, Matthieu ; Marangoni, Elisabetta ; Chavrier, Philippe ; Le Tourneau, Christophe ; Kamal, Maud ; Pasmant, Eric ; Vidaud, Michel ; Servant, Nicolas ; Reyal, Fabien ; Meseure, Dider ; Vincent-Salomon, Anne ; Fre, Silvia ; Margueron, Raphaël

Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight [...]

Menée dans le cadre du projet "International Cancer Genome Consortium", cette étude compare les techniques de séquençage, les outils d'analyse et les méthodes de validation mis en oeuvre par les participants

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing

Alioto, Tyler S. ; Buchhalter, Ivo ; Derdak, Sophia ; Hutter, Barbara ; Eldridge, Matthew D. ; Hovig, Eivind ; Heisler, Lawrence E. ; Beck, Timothy A. ; Simpson, Jared T. ; Tonon, Laurie ; Sertier, Anne-Sophie ; Patch, Ann-Marie ; Jager, Natalie ; Ginsbach, Philip ; Drews, Ruben ; Paramasivam, Nagarajan ; Kabbe, Rolf ; Chotewutmontri, Sasithorn ; Diessl, Nicolle ; Previti, Christopher ; Schmidt, Sabine ; Brors, Benedikt ; Feuerbach, Lars ; Heinold, Michael ; Grobner, Susanne ; Korshunov, Andrey ; Tarpey, Patrick S. ; Butler, Adam P. ; Hinton, Jonathan ; Jones, David ; Menzies, Andrew ; Raine, Keiran ; Shepherd, Rebecca ; Stebbings, Lucy ; Teague, Jon W. ; Ribeca, Paolo ; Giner, Francesc Castro ; Beltran, Sergi ; Raineri, Emanuele ; Dabad, Marc ; Heath, Simon C. ; Gut, Marta ; Denroche, Robert E. ; Harding, Nicholas J. ; Yamaguchi, Takafumi N. ; Fujimoto, Akihiro ; Nakagawa, Hidewaki ; Quesada, Victor ; Valdes-Mas, Rafael ; Nakken, Sigve ; Vodak, Daniel ; Bower, Lawrence ; Lynch, Andrew G. ; Anderson, Charlotte L. ; Waddell, Nicola ; Pearson, John V. ; Grimmond, Sean M. ; Peto, Myron ; Spellman, Paul ; He, Minghui ; Kandoth, Cyriac ; Lee, Semin ; Zhang, John ; Letourneau, Louis ; Ma, Singer ; Seth, Sahil ; Torrents, David ; Xi, Liu ; Wheeler, David A. ; López-Otín, Carlos ; Campo, Elias ; Campbell, Peter J. ; Boutros, Paul C. ; Puente, Xose S. ; Gerhard, Daniela S. ; Pfister, Stefan M. ; McPherson, John D. ; Hudson, Thomas J. ; Schlesner, Matthias ; Lichter, Peter ; Eils, Roland ; Jones, David T. W. ; Gut, Ivo G.

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free [...]