A partir de données portant sur 200 paires d'échantillons de tissu tumoral et de tissu sain issues du projet "The Cancer Genome Atlas" (11 types de cancer), cette étude identifie un ensemble d'insertions somatiques de rétrotransposons, principalement dans les carcinomes de l'endomètre, de la tête et du cou, du côlon-rectum et du poumon

Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing

Helman, Elena ; Lawrence, Michael L. ; Stewart, Chip ; Sougnez, Carrie ; Getz, Gad ; Meyerson, Matthew

Retrotransposons comprise over 40% of the human genome and constitute a major source of genetic variation. Somatic retrotransposon insertions have been reported in cancer. Here we present a comprehensive analysis of somatic retrotransposon insertions across multiple cancers. We applied TranspoSeq, a computational framework that identifies somatic retrotransposon insertions from massively parallel sequencing data, to whole-genome sequences from 200 tumor/normal pairs across 11 cancer types as [...]

Menée à partir d'échantillons tumoraux prélevés sur 50 patientes atteintes d'un cancer micropapillaire invasif pur (CMIP) du sein et sur 27 patientes atteintes d'un carcinome canalaire invasif, cette étude française identifie un ensemble de mutations somatiques et d'autres anomalies biologiques (modifications épigénétiques, altérations du stroma) spécifiques du CMIP

Polarity gene alterations in pure invasive micropapillary carcinomas of the breast

Gruel, Nadege ; Benhamo, Vanessa ; Bhalshankar, Jaydutt ; Popova, Tatiana ; Freneaux, Paul ; Arnould, Laurent ; Mariani, Odette ; Stern, Marc-Henri ; Raynal, Virginie ; Sastre-Garau, Xavier ; Rouzier, Roman ; Delattre, Olivier ; Vincent-Salomon, Anne

INTRODUCTION:Pure invasive micropapillary carcinoma (IMPC) is a special type of breast carcinoma characterized by clusters of cells presenting polarity abnormalities. The biological alterations underlying this pattern remain unknown. METHODS:Pangenomic analysis (SNP6.0 Affymetrix, n = 39), TP53 (n = 43) and PIK3CA (n = 41) sequencing in a series of IMPC were performed. A subset of cases was also analysed with whole-exome (n = 4) and RNA sequencing (n = 6). Copy number alteration profiles were [...]

Menée à partir de 34 échantillons tumoraux prélevés sur des patients atteints d'un médulloblastome et de 5 tumeurs murines, cette étude identifie un ensemble d'anomalies de nature épigénétique associées au développement de la maladie

Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

Hovestadt, Volker ; Jones, David T. W. ; Picelli, Simone ; Wang, Wei ; Kool, Marcel ; Northcott, Paul A. ; Sultan, Marc ; Stachurski, Katharina ; Ryzhova, Marina ; Warnatz, Hans-Jörg ; Ralser, Meryem ; Brun, Sonja ; Bunt, Jens ; Jager, Natalie ; Kleinheinz, Kortine ; Erkek, Serap ; Weber, Ursula D. ; Bartholomae, Cynthia C. ; von Kalle, Christof ; Lawerenz, Chris ; Eils, Jürgen ; Koster, Jan ; Versteeg, Rogier ; Milde, Till ; Witt, Olaf ; Schmidt, Sabine ; Wolf, Stephan ; Pietsch, Torsten ; Rutkowski, Stefan ; Scheurlen, Wolfram ; Taylor, Michael D. ; Brors, Benedikt ; Felsberg, Jörg ; Reifenberger, Guido ; Borkhardt, Arndt ; Lehrach, Hans ; Wechsler-Reya, Robert J. ; Eils, Roland ; Yaspo, Marie-Laure ; Landgraf, Pablo ; Korshunov, Andrey ; Zapatka, Marc ; Radlwimmer, Bernhard ; Pfister, Stefan M. ; Lichter, Peter

Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still [...]

Menée à l'aide de modèles murins et de données portant sur des patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence des mécanismes par lesquels une perte d'expression de l'E-cadhérine favorise la croissance tumorale et montre qu'elle est associée à un pronostic défavorable

Evidence for a role of E-cadherin in suppressing liver carcinogenesis in mice and men

Schneider, Marlon R. ; Hiltwein, Felix ; Grill, Jessica ; Blum, Helmut ; Krebs, Stefan ; Klanner, Andrea ; Bauersachs, Stefan ; Bruns, Christiane ; Longerich, Thomas ; Horst, David ; Kriegl, Lydia ; de Toni, Enrico ; Herbst, Andreas ; Kolligs, Frank T.

The cell adhesion molecule E-cadherin has critical functions in development and carcinogenesis. Impaired expression of E-cadherin has been associated with disrupted tissue homeostasis, progression of cancer and a worse patient prognosis. So far, the role of E-cadherin in homeostasis and carcinogenesis of the liver is not well understood. By use of a mouse model with liver-specific deletion of E-cadherin and administration of the carcinogen diethylnitrosamin, we demonstrate that loss of [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels le micro-ARN miR-28 exerce une fonction de suppresseur de tumeurs dans les lymphomes de Burkitt

microRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas

Schneider, Christof ; Setty, Manu ; Holmes, Antony B. ; Maute, Roy L. ; Leslie, Christina S. ; Mussolin, Lara ; Rosolen, Angelo ; Dalla-Favera, Riccardo ; Basso, Katia

Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (B-NHL), which originates from germinal center (GC) B cells and harbors translocations deregulating v-myc avian myelocytomatosis viral oncogene homolog (MYC). A comparative analysis of microRNAs expressed in normal and malignant GC B cells identified microRNA 28 (miR-28) as significantly down-regulated in BL, as well as in other GC-derived B-NHL. We show that reexpression of miR-28 impairs cell proliferation and clonogenic [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par l'enzyme Dnmt3a dans le développement d'une tumeur intestinale

Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 3a

Weis, B. ; Schmidt, J. ; Maamar, H. ; Raj, A. ; Lin, H. ; Toth, C. ; Riedmann, K. ; Raddatz, G. ; Seitz, H. K. ; Ho, A. D. ; Lyko, F. ; Linhart, H. G.

Aberrant de novo methylation of DNA is considered an important mediator of tumorigenesis. To investigate the role of de novo DNA methyltransferase 3a (Dnmt3a) in intestinal tumor development, we analyzed the expression of Dnmt3a in murine colon crypts, murine colon adenomas and human colorectal cancer using RNA fluorescence in situ hybridization (FISH), quantitative PCR and immunostaining. Following conditional deletion of Dnmt3a in the colon of APC(Min/+) mice, we analyzed tumor numbers, [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en induisant une activation aberrante de STAT3, la perte du gène PTPRD favorise le développement d'un gliome

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz, Berenice ; Fabius, Armida W. M. ; Wu, Wei H. ; Pedraza, Alicia ; Brennan, Cameron W. ; Schultz, Nikolaus ; Pitter, Kenneth L. ; Bromberg, Jacqueline F. ; Huse, Jason T. ; Holland, Eric C. ; Chan, Timothy A.

PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse [...]

Cet article passe en revue les travaux récents établissant un lien entre hypoxie, matrice extracellulaire et processus métastatique

Hypoxia and the extracellular matrix: drivers of tumour metastasis

Gilkes, Daniele M. ; Semenza, Gregg L. ; Wirtz, Denis

Of the deaths attributed to cancer, 90% are due to metastasis, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that hypoxia and the extracellular matrix (ECM) might have crucial roles in metastasis. During tumour evolution, changes in the composition and the overall content of the ECM reflect both its biophysical and biological properties and these strongly influence tumour and stromal cell properties, such as proliferation and motility. Originally thought [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la protéine PIK3R3 favorise le processus métastatique d'un cancer colorectal

PIK3R3 induces epithelial-to-mesenchymal transition and promotes metastasis in colorectal cancer

Wang, Guihua ; Yang, Xi ; Li, Chuan ; Cao, Xiaonian ; Luo, Xuelai ; Hu, Junbo

Class IA phosphatidylinositol 3-kinase (PI3K) plays an essential role in the invasion and metastasis of cancer. However, the mechanisms and specific functions of PI3K isoforms in tumor invasion and metastasis are not fully understood. We evaluated the role of PIK3R3, a PI3K regulatory subunit encoded by the PIK3R3 gene, in colorectal cancer (CRC) invasion and metastasis. Clinic specimens and cell lines data shows the expression level of PIK3R3 is associated with CRC metastasis. Over-expression [...]

Menée sur des lignées cellulaires de cancer du sein triplement négatif, cette étude met en évidence des mécanismes par lesquels le facteur de transcription AP-1 favorise le processus invasif

Genome-wide profiling of AP-1 regulated transcription provides insights into the invasiveness of triple-negative breast cancer

Zhao, Chunyan ; Qiao, Yichun ; Jonsson, Philip ; Wang, Jian ; Xu, Li ; Rouhi, Pegah ; Sinha, Indranil ; Cao, Yihai ; Williams, Cecilia ; Dahlman-Wright, Karin

Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via la régulation de l'épissage alternatif, la protéine hnRNPM favorise le processus métastatique d'un cancer du sein

Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

Xu, Yilin ; Gao, Xin D. ; Lee, Jae-Hyung ; Huang, Huilin ; Tan, Haiyan ; Ahn, Jaegyoon ; Reinke, Lauren M. ; Peter, Marcus E. ; Feng, Yue ; Gius, David ; Siziopikou, Kalliopi P. ; Peng, Junmin ; Xiao, Xinshu ; Cheng, Chonghui

Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial–mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that [...]

Cet article passe en revue les travaux récents sur les causes de la diversité génétique intratumorale dans le cancer du sein, puis analyse les conséquences à en tirer pour la prise en charge des patientes

Breast cancer intra-tumor heterogeneity

Martelotto, Luciano ; Ng, Charlotte ; Piscuoglio, Salvatore ; Weigelt, Britta ; Reis-Filho, Jorge

In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra-tumor genetic heterogeneity in breast cancers; however, its basis is yet to be fully defined. Two of the most widely evoked concepts to explain the origin of heterogeneity within tumors are the cancer stem cell hypothesis and the clonal evolution model. Although [...]