Cet article passe en revue les travaux récents, menés à l'aide de techniques de séquençage de prochaine génération, ayant identifié de nouvelles altérations génétiques associées aux carcinomes hépatocellulaires

Next generation sequencing reveals genetic landscape of hepatocellular carcinomas

Li, Shuyu ; Mao, Mao

Liver cancer is one of most deadly cancers worldwide. Hepatocellualr carcinoma (HCC) represents a major histological subtype of liver cancers. As cancer is a genetic disease, genetic lesions play a major role in HCC tumorigenesis and progression. Although significant progress has been made to uncover genetic alterations in HCCs, our understanding of genetics involved in the initiation and progression of HCC is far from complete. Next generation sequencing (NGS) has provided a new paradigm in [...]

Cet article passe en revue les travaux récents sur l'hétérogénéité des génomes de cancer et leur dynamique évolutive

Evolution of the cancer genome

Yates, Lucy R. ; Campbell, Peter J.

The advent of massively parallel sequencing technologies has allowed the characterization of cancer genomes at an unprecedented resolution. Investigation of the mutational landscape of tumours is providing new insights into cancer genome evolution, laying bare the interplay of somatic mutation, adaptation of clones to their environment and natural selection. These studies have demonstrated the extent of the heterogeneity of cancer genomes, have allowed inferences to be made about the forces [...]

Menée in vitro à partir de l'observation d'une population de fibroblastes immortalisés sur 300 générations, cette étude met en évidence l'évolution différenciée de polymorphismes épigénomiques selon la nature, cancéreuse ou normale, des tissus

Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues

Landan, Gilad ; Cohen, Netta Mendelson ; Mukamel, Zohar ; Bar, Amir ; Molchadsky, Alina ; Brosh, Ran ; Horn-Saban, Shirley ; Zalcenstein, Daniela Amann ; Goldfinger, Naomi ; Zundelevich, Adi ; Gal-Yam, Einav Nili ; Rotter, Varda ; Tanay, Amos

DNA methylation has been comprehensively profiled in normal and cancer cells, but the dynamics that form, maintain and reprogram differentially methylated regions remain enigmatic. Here, we show that methylation patterns within populations of cells from individual somatic tissues are heterogeneous and polymorphic. Using in vitro evolution of immortalized fibroblasts for over 300 generations, we track the dynamics of polymorphic methylation at regions developing significant differential [...]

Menée sur des échantillons prélevés sur 139 patients atteints d'une leucémie lymphocytaire chronique, cette étude identifie des signatures de méthylation de l'ADN associées à divers sous-types de la maladie

Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia

Kulis, Marta ; Heath, Simon ; Bibikova, Marina ; Queiros, Ana C. ; Navarro, Alba ; Clot, Guillem ; Martinez-Trillos, Alejandra ; Castellano, Giancarlo ; Brun-Heath, Isabelle ; Pinyol, Magda ; Barberan-Soler, Sergio ; Papasaikas, Panagiotis ; Jares, Pedro ; Bea, Silvia ; Rico, Daniel ; Ecker, Simone ; Rubio, Miriam ; Royo, Romina ; Ho, Vincent ; Klotzle, Brandy ; Hernandez, Lluis ; Conde, Laura ; Lopez-Guerra, Monica ; Colomer, Dolors ; Villamor, Neus ; Aymerich, Marta ; Rozman, Maria ; Bayes, Monica ; Gut, Marta ; Gelpi, Josep L. ; Orozco, Modesto ; Fan, Jian-Bing ; Quesada, Victor ; Puente, Xose S. ; Pisano, David G. ; Valencia, Alfonso ; Lopez-Guillermo, Armando ; Gut, Ivo ; López-Otín, Carlos ; Campo, Elias ; Martin-Subero, Jose I.

We have extensively characterized the DNA methylomes of 139 patients with chronic lymphocytic leukemia (CLL) with mutated or unmutated IGHV and of several mature B-cell subpopulations through the use of whole-genome bisulfite sequencing and high-density microarrays. The two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B-cell subpopulations. DNA hypomethylation in the gene body, targeting mostly enhancer sites, was the [...]

Menée sur 353 échantillons prélevés, avant le traitement, sur des patients atteints d'une leucémie lymphocytaire chronique et inclus dans l'essai CCL8, cette étude identifie de nouvelles altérations génomiques associées à cette maladie

High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations

Edelmann, Jennifer ; Holzmann, Karlheinz ; Miller, Florian ; Winkler, Dirk ; Bühler, Andreas ; Zenz, Thorsten ; Bullinger, Lars ; Kühn, Michael W. M. ; Gerhardinger, Andreas ; Bloehdorn, Johannes ; Radtke, Ina ; Su, Xiaoping ; Ma, Jing ; Pounds, Stanley ; Hallek, Michael ; Lichter, Peter ; Korbel, Jan ; Busch, Raymonde ; Mertens, Daniel ; Downing, James R. ; Stilgenbauer, Stephan ; Döhner, Hartmut

To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism (SNP)-array analysis (Affymetrix 6.0) on 353 samples from untreated patients entered on the CLL8 treatment trial. Based on paired-sample analysis (n=144), a mean of 1.8 copy number alterations (CNAs) per case were identified; about 60% of cases carried no CNAs other than those detected by fluorescence in-situ hybridization analysis. Copy-neutral loss-of-heterozygosity was detected [...]

Menée sur 19 lignées cellulaires et des échantillons de tissus sains et tumoraux prélevés sur 3 patients atteints d'un cancer du poumon, cette étude met en évidence des mutations de gènes impliqués dans la régulation épigénétique et des mutations associées à un épissage alternatif anormal spécifique du cancer

Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events

Liu, Jinfeng ; Lee, William ; Jiang, Zhaoshi ; Chen, Zhongqiang ; Jhunjhunwala, Suchit ; Haverty, Peter M ; Gnad, Florian ; Guan, Yinghui ; Gilbert, Houston ; Stinson, Jeremy ; Klijn, Christiaan ; Guillory, Joseph ; Bhatt, Deepali ; Vartanian, Steffan ; Walter, Kimberly ; Chan, Jocelyn ; Holcomb, Thomas ; Dijkgraaf, Peter ; Johnson, Stephanie ; Koeman, Julie ; Minna, John D ; Gazdar, Adi F ; Stern, Howard M ; Hoeflich, Klaus P ; Wu, Thomas D ; Settleman, Jeff ; de Sauvage, Frederic J ; Gentleman, Robert C ; Neve, Richard M ; Stokoe, David ; Modrusan, Zora ; Seshagiri, Somasekar ; Shames, David S ; Zhang, Zemin

Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and 3 lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including [...]

Menée sur des échantillons de tissus sains et tumoraux prélevés sur 16 patients atteints d'un cancer colorectal, cette étude met en évidence la fréquence d'insertions de rétrotransposons L1, ainsi que leurs gènes cibles, dans les tissus tumoraux

Extensive somatic L1 retrotransposition in colorectal tumors

Solyom, Szilvia ; Ewing, Adam D. ; Rahrmann, Eric P. ; Doucet, Tara T. ; Nelson, Heather H. ; Burns, Michael B. ; Harris, Reuben S. ; Sigmon, David F. ; Casella, Alex ; Erlanger, Bracha ; Wheelan, Sarah ; Upton, Kyle R. ; Shukla, Ruchi ; Faulkner, Geoffrey J. ; Largaespada, David A. ; Kazazian, Haig H.

L1 retrotransposons comprise 17% of the human genome, and are its only autonomous mobile elements. Although L1-induced insertional mutagenesis causes Mendelian disease, their mutagenic load in cancer has been elusive. Using L1-targeted re-sequencing of 16 colorectal tumor and matched normal DNAs, we found that certain cancers were excessively mutagenized by human-specific L1s, while no verifiable insertions were present in normal tissues. We confirmed de novo L1 insertions in malignancy by both [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en se liant à PKM2, la sérine induit une surexpression de cette enzyme dans les cellules cancéreuses et favorise ainsi la prolifération cellulaire

Serine is a natural ligand and allosteric activator of pyruvate kinase M2

Chaneton, Barbara ; Hillmann, Petra ; Zheng, Liang ; Martin, Agnes C. L. ; Maddocks, Oliver D. K. ; Chokkathukalam, Achuthanunni ; Coyle, Joseph E. ; Jankevics, Andris ; Holding, Finn P. ; Vousden, Karen H. ; Frezza, Christian ; O/'Reilly, Marc ; Gottlieb, Eyal

Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation. Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine. Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels des altérations du gène MLL2, impliqué dans la régulation épigénétique de la transcription génétique, favorisent la tumorigenèse

Global identification of MLL2-targeted loci reveals MLL2’s role in diverse signaling pathways

Guo, Changcun ; Chang, Chun-Chi ; Wortham, Matthew ; Chen, Lee H. ; Kernagis, Dawn N. ; Qin, Xiaoxia ; Cho, Young-Wook ; Chi, Jen-Tsan ; Grant, Gerald A. ; McLendon, Roger E. ; Yan, Hai ; Ge, Kai ; Papadopoulos, Nickolas ; Bigner, Darell D. ; He, Yiping

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en se liant à CD45, la galectine 3 régule l'apoptose dans les lymphomes diffus à grandes cellules B

Galectin-3 binds to CD45 on diffuse large B cell lymphoma cells to regulate susceptibility to cell death

Clark, Mary C. ; Pang, Mabel ; Hsu, Daniel K. ; Liu, Fu-Tong ; de Vos, Sven ; Gascoyne, Randy D. ; Said, Jonathan ; Baum, Linda G.

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma and an aggressive malignancy. Galectin-3 (gal-3), the only anti-apoptotic member of the galectin family, is overexpressed in DLBCL. While gal-3 can localize to intracellular sites, gal-3 is secreted by DLBCL cells and binds back to the cell surface in a carbohydrate-dependent manner. The major counterreceptor for gal-3 on DLBCL cells was identified as the transmembrane tyrosine phosphatase CD45. Removal of cell [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel la protéase Nexin 1 joue un rôle inhibiteur de la signalisation Hedgehog dans les adénocarcinomes de la prostate

Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma

McKee, Chad M. ; Xu, Danmei ; Cao, Yunhong ; Kabraji, Sheheryar ; Allen, Danny ; Kersemans, Veerle ; Beech, John ; Smart, Sean ; Hamdy, Freddie ; Ishkanian, Adrian ; Sykes, Jenna ; Pintile, Melania ; Milosevic, Michael ; van der Kwast, Theodorus ; Zafarana, Gaetano ; Ramnarine, Varune Rohan ; Jurisica, Igor ; Mallof, Chad ; Lam, Wan ; Bristow, Robert G. ; Muschel, Ruth J.

Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) [...]

Menée in vitro et in vivo grâce à une technique de mutagenèse par transposons, cette étude identifie des gènes associés à la transformation de cellules souches neurales en cellules initiatrices de glioblastome

Transposon mutagenesis identifies genes that transform neural stem cells into glioma-initiating cells

Koso, Hideto ; Takeda, Haruna ; Yew, Christopher Chin Kuan ; Ward, Jerrold M. ; Nariai, Naoki ; Ueno, Kazuko ; Nagasaki, Masao ; Watanabe, Sumiko ; Rust, Alistair G. ; Adams, David J. ; Copeland, Neal G. ; Jenkins, Nancy A.

Neural stem cells (NSCs) are considered to be the cell of origin of glioblastoma multiforme (GBM). However, the genetic alterations that transform NSCs into glioma-initiating cells remain elusive. Using a unique transposon mutagenesis strategy that mutagenizes NSCs in culture, followed by additional rounds of mutagenesis to generate tumors in vivo, we have identified genes and signaling pathways that can transform NSCs into glioma-initiating cells. Mobilization of Sleeping Beauty transposons in [...]

Menée sur des lignées cellulaires de neuroblastome, cette étude met en évidence des mécanismes spécifiques de division cellulaire asymétrique et d'héritage du centrosome

Evidence of asymmetric cell division and centrosome inheritance in human neuroblastoma cells

Izumi, Hideki ; Kaneko, Yasuhiko

Asymmetric cell division (ACD) is believed to be a physiological event that occurs during development and tissue homeostasis in a large variety of organisms. ACD produces two unequal daughter cells, one of which resembles a multipotent stem and/or progenitor cell, whereas the other has potential for differentiation. Although recent studies have shown that the balance between self-renewal and differentiation potentials is precisely controlled and that alterations in the balance may lead to [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la signalisation NF-κB régule l'accumulation de cellules souches mésenchymateuses dans les localisations tumorales

NF-κB activity regulates mesenchymal stem cell accumulation at tumor sites

Uchibori, Ryosuke ; Tsukahara, Tomonori ; Mizuguchi, Hiroyuki ; Saga, Yasushi ; Urabe, Masashi ; Mizukami, Hiroaki ; Kume, Akihiro ; Ozawa, Keiya

Mesenchymal stem cells (MSCs) accumulate at tumor sites when injected into tumor-bearing mice, perhaps offering cellular vectors for cancer-targeted gene therapy. However, the molecular mechanisms involved in MSC targeting to tumors are presently little understood. We focused on MSC-endothelial cell (EC) adhesion following tumor necrosis factor-α (TNF-α) stimulation in an attempt to elucidate these mechanisms. Interestingly, stimulation of MSCs with TNF-α enhanced the adhesion of MSCs to ECs in [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel une protéine, l'alpha-catuline, favorise le processus métastatique dans le cancer du poumon non à petites cellules

α-catulin drives metastasis by activating ILK and driving an avß3 integrin signaling axis

Liang, Chen-Hsien ; Chiu, Szu-ying ; Hsu, I-Ling ; Wu, Yi-Ying ; Tsai, Yao-Tsung ; Ke, Jhen-Yu ; Pan, Szu-Hua ; Hsu, Yi-Chiung ; Li, Ker-Chau ; Yang, Pan-Chyr ; Chen, Yuh-Ling ; Hong, Tse-Ming

α-catulin is oncoprotein that help sustains proliferation by preventing cellular senescence. Here we report that α-catulin also drives malignant invasion and metastasis. α-catulin was upregulated in highly invasive non-small cell lung cancer (NSCLC) cell lines, where its ectopic expression or shRNA-mediated attenuation enhanced or limited invasion or metastasis, respectively. α-catulin interacted with integrin-linked kinase (ILK), a serine/threonine protein kinase implicated in cancer cell [...]

Menée à l'aide de modèles murins, cette étude montre que l'endotrophine, un produit du clivage d'une chaîne de collagène dans les adipocytes du micro-environnement mammaire, favorise la progression d'un cancer du sein

Adipocyte-derived endotrophin promotes malignant tumor progression

Park, Jiyoung ; Scherer, Philipp E.

Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6α3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation [...]

Cet article présente les travaux récents sur la terminologie et les paramètres pertinents à utiliser dans les études sur les cellules souches cancéreuses

Cancer stem cell definitions and terminology: the devil is in the details

Valent, Peter ; Bonnet, Dominique ; De Maria, Ruggero ; Lapidot, Tsvee ; Copland, Mhairi ; Melo, Junia V. ; Chomienne, Christine ; Ishikawa, Fumihiko ; Schuringa, Jan Jacob ; Stassi, Giorgio ; Huntly, Brian ; Herrmann, Harald ; Soulier, Jean ; Roesch, Alexander ; Schuurhuis, Gerrit Jan ; Wohrer, Stefan ; Arock, Michel ; Zuber, Johannes ; Cerny-Reiterer, Sabine ; Johnsen, Hans E. ; Andreeff, Michael ; Eaves, Connie

The cancer stem cell (CSC) concept has important therapeutic implications, but its investigation has been hampered both by a lack of consistency in the terms used for these cells and by how they are defined. Evidence of their heterogeneous origins, frequencies and their genomic, as well as their phenotypic and functional, properties has added to the confusion and has fuelled new ideas and controversies. Participants in The Year 2011 Working Conference on CSCs met to review these issues and to [...]

Cette étude présente un modèle d'évolution tumorale alimenté par des données d'incidence des cancers en fonction de l'âge

Impact of Tumor Progression on Cancer Incidence Curves

Luebeck, E. Georg ; Curtius, Kit ; Jeon, Jihyoun ; Hazelton, William D.

Cancer arises through a multistage process, but it is not fully clear how this process influences the age-specific incidence curve. Studies of colorectal and pancreatic cancer using the multistage-clonal-expansion (MSCE) model have identified two phases of the incidence curves. One phase is linear beginning about age of 60, suggesting that at least two rare rate-limiting mutations occur prior to clonal expansion of premalignant cells. A second phase is exponential, seen in earlier-onset cancers [...]