Cet article passe en revue les travaux récents sur le phénomène de chromothripsis, qui implique de multiples réarrangements chromosomiques au cours d'un unique événement cellulaire

Chromothripsis and cancer: causes and consequences of chromosome shattering

Forment, Josep V. ; Kaidi, Abderrahmane ; Jackson, Stephen P.

Genomic alterations that lead to oncogene activation and tumour suppressor loss are important driving forces for cancer development. Although these changes can accumulate progressively during cancer evolution, recent studies have revealed that many cancer cells harbour chromosomes bearing tens to hundreds of clustered genome rearrangements. In this Review, we describe how this striking phenomenon, termed chromothripsis, is likely to arise through chromosome breakage and inaccurate reassembly. [...]

Menée sur 50 échantillons prélevés sur des patients atteints d'une leucémie myéloïde aiguë et à partir de données portant sur 391 cas, cette étude identifie un ensemble d'altérations de gènes impliqués dans le remodelage de la chromatine et l'épissage

Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin-remodeling and splicing

Dolnik, Anna ; Engelmann, Julia C. ; Scharfenberger-Schmeer, Maren ; Mauch, Julian ; Kelkenberg-Schade, Sabine ; Haldemann, Berit ; Fries, Tamara ; Krönke, Jan ; Kühn, Michael W. M. ; Paschka, Peter ; Kayser, Sabine ; Wolf, Stephan ; Gaidzik, Verena I. ; Schlenk, Richard F. ; Rücker, Frank G. ; Döhner, Hartmut ; Lottaz, Claudio ; Döhner, Konstanze ; Bullinger, Lars

Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major [...]

Menée sur 200 échantillons tumoraux prélevés sur des patients coréens atteints d'un adénocarcinome du poumon, cette étude de séquençage de l'ARN identifie des mutations somatiques et des variants de transcription, notamment en association avec le statut tabagique des patients

The transcriptional landscape and mutational profile of lung adenocarcinoma

Seo, Jeong-Sun ; Ju, Young Seok ; Lee, Won-Chul ; Shin, Jong-Yeon ; Lee, June Koo ; Bleazard, Thomas ; Lee, Junho ; Jung, Yoo Jin ; Kim, Jung-Oh ; Shin, Jung-Young ; Yu, Saet-Byeol ; Kim, Jihye ; Lee, Eung-Ryoung ; Kang, Chang-Hyun ; Park, In-Kyu ; Rhee, Hwanseok ; Lee, Se-Hoon ; Kim, Jong-Il ; Kang, Jin-Hyoung ; Kim, Young Tae

All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in [...]

Menée in vitro et in vivo, cette étude suggère qu'une protéine de la famille des métallothionéines, MT1M, joue un rôle de suppresseur de tumeurs dans les carcinomes hépatocellulaires

Metallothionein MT1M is a tumor suppressor of human hepatocellular carcinomas

Mao, Jun ; Yu, Hongxiu ; Wang, Chenji ; Sun, Luhong ; Jiang, Wei ; Zhang, Pingzhao ; Qianyi, Xiao ; Saiyin, Hexige ; Zhu, Jingde ; Chen, Taoyang ; Roberts, Lewis R. ; Huang, Haojie ; Yu, Long

Members of the metallothionein (MT) family are short, cysteine-rich proteins involved in metal metabolism and detoxification, suggesting that MT proteins protect cells from damage caused by electrophilic carcinogens and thereby constitute a critical surveillance system against carcinogenesis. However, the roles of MT proteins in human hepatocellular carcinoma (HCC) are not fully understood. We identified a member of the metallothionein family, termed MT1M. MT1M is expressed in various normal [...]

Cet article passe en revue les travaux récents sur le rôle d'une activité anormale de l'ARN polymérase I dans la tumorigenèse

Revisiting the Nucleolus: From Marker to Dynamic Integrator of Cancer Signaling

Ruggero, Davide

Key signaling pathways (such as phosphoinositide 3-kinase, Myc, and RAS) act as sensors of energy, stress, and nutrient availability and integrate these inputs to directly control ribosome production and gene expression at the translational level. This activity is normally directly coupled to cell growth, division, and survival. However, it remains poorly understood the extent to which changes in ribosome number and nucleolar integrity downstream of these key signaling pathways contribute to [...]

Menée sur des échantillons prélevés sur des patients atteints d'un mélanome et à l'aide de modèles murins, cette étude met en évidence un mécanisme de nature épigénétique par lequel la perte de la méthylation de l'ADN des cytosines en position 5 favorise le développement de la maladie

Loss of 5-Hydroxymethylcytosine Is an Epigenetic Hallmark of Melanoma

Lian, Christine Guo ; Xu, Yufei ; Ceol, Craig ; Wu, Feizhen ; Larson, Allison ; Dresser, Karen ; Xu, Wenqi ; Tan, Li ; Hu, Yeguang ; Zhan, Qian ; Lee, Chung-wei ; Hu, Di ; Lian, Bill Q ; Kleffel, Sonja ; Yang, Yijun ; Neiswender, James ; Khorasani, Abraham J ; Fang, Rui ; Lezcano, Cecilia ; Duncan, Lyn M ; Scolyer, Richard A ; Thompson, John F ; Kakavand, Hojabr ; Houvras, Yariv ; Zon, Leonard I ; Mihm, Martin C ; Kaiser, Ursula B ; Schatton, Tobias ; Woda, Bruce A ; Murphy, George F ; Shi, Yujiang G

DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that loss of 5-hmC is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that [...]

Menée à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel, en régulant l'apoptose, le micro-ARN 33b joue un rôle de suppresseur de tumeurs dans les myélomes multiples

Investigational agent MLN9708/2238 targets tumor suppressor microRNA-33b in MM cells

Tian, Ze ; Zhao, Jian-Jun ; Tai, Yu-Tzu ; Amin, Samir B. ; Hu, Yiguo ; Richardson, Paul ; Chauhan, Dharminder ; Anderson, Kenneth C.

MicroRNA (miRNAs) play a critical role in tumor pathogenesis either as oncogenes or tumor suppressor genes. However, the role of miRNA and their regulation in response to proteasome inhibitors in multiple myeloma (MM) is unclear. miRNA profiling in proteasome inhibitor MLN2238-treated MM.1S MM cells shows upregulation of miR-33b. Mechanistic study indicates that induction of miR-33b is predominantly via transcriptional regulation. Examination of miR33b in patient MM cells showed a [...]

Menée sur 117 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer épithélial de l'ovaire, in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en inhibant un gène impliqué dans l'apoptose, le gène SUZ12 favorise la prolifération des cellules cancéreuses

SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK

Li, Hua ; Cai, Qi ; Wu, Hong ; Vathipadiekal, Vinod ; Dobbin, Zachary C. ; Li, Tianyu ; Hua, Xiang ; Landen, Charles N. ; Birrer, Michael J. ; Sanchez-Beato, Margarita ; Zhang, Rugang

Epithelial ovarian cancer (EOC) ranks first as the cause of death for gynecological cancers in the United States. SUZ12 is a component of the polycomb repressive complex 2 (PRC2) and is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). The role of SUZ12 in EOC has never been investigated. Here we show that SUZ12 is expressed at significantly higher levels in human EOC (n=117) compared with either normal human ovarian surface [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en modulant l'expression du micro-ARN 23a, la protéine CREB favorise la formation d'un gliome

cAMP response element-binding protein promotes gliomagenesis by modulating the expression of oncogenic microRNA-23a

Tan, Xiaochao ; Wang, Shan ; Zhu, Liyuan ; Wu, Chao ; Yin, Bin ; Zhao, Jizong ; Yuan, Jiangang ; Qiang, Boqin ; Peng, Xiaozhong

Gliomas are the most common and deadly type of primary brain tumor. In this study, we showed that cAMP response element-binding protein (CREB), a proto-oncogenic transcription factor that is overexpressed in gliomas, can promote gliomagenesis by modulating the expression of oncogenic microRNA-23a (mir-23a). First, we found that CREB is highly expressed in glioma tissues and cell lines. CREB is also essential for glioma cell growth and cell survival in vitro and is critical for gliomagenesis in [...]

Menée sur 60 échantillons prélevés sur des patientes présentant une néoplasie cervicale intra-épithéliale de haut grade et sur des lignées cellulaires, cette étude identifie des anomalies chromosomiques contribuant à une cancérogenèse induite par le papillomavirus humain et suggère que les gènes EYA2 et hsa-miR-375 jouent respectivement un rôle d'oncogène et de suppresseur de tumeurs

Focal aberrations indicate EYA2 and hsa-miR-375 as oncogene and tumor suppressor in cervical carcinogenesis

Bierkens, Mariska ; Krijgsman, Oscar ; Wilting, Saskia M. ; Bosch, Leontien ; Jaspers, Annelieke ; Meijer, Gerrit A. ; Meijer, Chris J. L. M. ; Snijders, Peter J. F. ; Ylstra, Bauke ; Steenbergen, Renske D. M.

Cervical cancer results from persistent infection with high-risk human papillomavirus (hrHPV). Common genetic aberrations in cervical (pre)cancers encompass large genomic regions with numerous genes, hampering identification of driver genes. This study aimed to identify genes functionally involved in HPV-mediated transformation by analysis of focal aberrations (<3 Mb) in high-grade cervical intraepithelial neoplasia (hgCIN). Focal chromosomal aberrations were determined in high-resolution array [...]

Menée à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel, en régulant l'expression de PDGF-B, le facteur HIF-1 favorise le processus métastatique d'un cancer du sein via le réseau lymphatique

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Schito, Luana ; Rey, Sergio ; Tafani, Marco ; Zhang, Huafeng ; Wong, Carmen Chak-Lui ; Russo, Andrea ; Russo, Matteo A. ; Semenza, Gregg L.

Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the [...]