Menée sur 43 ensembles de données de séquençage obtenus dans 5 types de cancers, cette étude identifie des insertions somatiques d'éléments transposables sur le génome et analyse leur rôle dans la tumorigenèse

Landscape of Somatic Retrotransposition in Human Cancers

Lee, Eunjung ; Iskow, Rebecca ; Yang, Lixing ; Gokcumen, Omer ; Haseley, Psalm ; Luquette, Lovelace J. ; Lohr, Jens G. ; Harris, Christopher C. ; Ding, Li ; Wilson, Richard K. ; Wheeler, David A. ; Gibbs, Richard A. ; Kucherlapati, Raju ; Lee, Charles ; Kharchenko, Peter V. ; Park, Peter J. ; The Cancer Genome Atlas Research Network

Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of [...]

Cet article passe en revue de nouvelles approches pour identifier, à partir de données obtenues par séquençage du génome, les altérations de gènes réellement impliquées dans le cancer

From cancer genomes to oncogenic drivers, tumour dependencies and therapeutic targets

Eifert, Cheryl ; Powers, R. Scott

The analysis of human cancer by genome sequencing and various types of arrays has proved that many tumours harbour hundreds of genes that are mutated or substantially altered by copy number changes. But how many of these changes are meaningful? And how can we exploit these massive data sets to yield new targets for cancer treatment? In this Opinion article, we describe emerging approaches that aim to determine which altered genes are actually contributing to cancer, as well as their potential [...]

Menée sur 6 échantillons de tissus corticosurrénaliens normaux, de 25 adénomes et 15 carcinomes corticosurrénaliens, cette étude analyse, à l'échelle du génome entier, les niveaux de méthylation de l'ADN

Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors

Fonseca, Annabelle L. ; Kugelberg, Johan ; Starker, Lee F. ; Scholl, Ute ; Choi, Murim ; Hellman, Per ; Akerstrom, Goran ; Westin, Gunnar ; Lifton, Richard P. ; Bjorklund, Peyman ; Carling, Tobias

The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in [...]

Cet article passe en revue les travaux récents en matière de génomique et d'épigénomique dans les carcinomes à cellules rénales

Genomics and Epigenomics of Renal Cell Carcinoma

Maher, Eamonn R.

Kidney cancer accounts for about 2% of all cancers and worldwide >250,000 new cases of kidney cancer are diagnosed each year. Renal cell carcinoma (RCC) is the most common form of adult kidney cancer and this review describes our current knowledge of the genetic and epigenetic basis of sporadic RCC. Though to date major advances in understanding the underlying the molecular basis of renal cell carcinoma (RCC) have often been derived from studies of rare familial forms of renal cell [...]

Menée sur des lignées cellulaires, cette étude met en évidence le rôle joué par le récepteur PD-1 dans la régulation du cycle cellulaire et l'inhibition de la prolifération des lymphocytes T

Selective Effects of PD-1 on Akt and Ras Pathways Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation

Patsoukis, Nikolaos ; Brown, Julia ; Petkova, Victoria ; Liu, Fang ; Li, Lequn ; Boussiotis, Vassiliki A.

The receptor programmed death 1 (PD-1) inhibits T cell proliferation and plays a critical role in suppressing self-reactive T cells, and it also compromises antiviral and antitumor responses. To determine how PD-1 signaling inhibits T cell proliferation, we used human CD4+ T cells to examine the effects of PD-1 signaling on the molecular control of the cell cycle. The ubiquitin ligase SCFSkp2 degrades p27kip1, an inhibitor of cyclin-dependent kinases (Cdks), and PD-1 blocked cell cycle [...]

Menée sur des lignées cellulaires de myélome multiple à l'aide d'anticorps monoclonaux (mapatumumab et lexatumumab), cette étude identifie un mécanisme de régulation de la mort cellulaire impliquant le récepteur DR5 et le gène p53

Cell death via DR5, but not DR4, is regulated by p53 in myeloma cells

Surget, Sylvanie ; Chiron, David ; Gomez-Bougie, Patricia ; Descamps, Géraldine ; Ménoret, Emmanuelle ; Bataille, Régis ; Moreau, Philippe ; Le Gouill, Steven ; Amiot, Martine ; Pellat-Deceunynck, Catherine

Myeloma cells are sensitive to TRAIL through both receptors, DR4 and DR5. Because p53 directly modulates expression of death receptors, we wondered whether p53 could modulate myeloma sensitivity to TRAIL. By using DR4 and DR5 agonistic human mAbs, respectively mapatumumab and lexatumumab, we show that TP53Wt HMCLs (n=9) but not TP53Abn HMCLs (n=22) were killed by lexatumumab (p<0.01) while TP53Abn HMCLs but not TP53Wt HMCLs were killed by mapatumumab (p<0.01). Compared with TP53Abn HMCLs, [...]

Menée in vitro, cette étude montre que la protéine Axin2 ne joue pas un rôle de suppresseur de tumeurs dans les cancers colorectaux mais qu'elle favorise la croissance tumorale via la régulation de la signalisation Wnt

Canonical Wnt suppressor, Axin2, promotes colon carcinoma oncogenic activity

Wu, Zhao-Qiu ; Brabletz, Thomas ; Fearon, Eric ; Willis, Amanda L. ; Hu, Casey Yuexian ; Li, Xiao-Yan ; Weiss, Stephen J.

Aberrant activation of canonical Wingless-type MMTV integration site family (Wnt) signaling is pathognomonic of colorectal cancers (CRC) harboring functional mutations in either adenomatous polyposis coli or β-catenin. Coincident with Wnt cascade activation, CRCs also up-regulate the expression of Wnt pathway feedback inhibitors, particularly the putative tumor suppressor, Axin2. Because Axin2 serves as a negative regulator of canonical Wnt signaling in normal cells, recent attention has [...]

Menée sur des lignées cellulaires, cette étude met en évidence le rôle joué par un plasmide de l'épisome, DDX5, dans la régulation de la réplication de l'ADN et la prolifération de certaines cellules de cancer du sein

DDX5 Regulates DNA Replication And Is Required For Cell Proliferation In A Subset Of Breast Cancer Cells

Mazurek, Anthony ; Luo, Weijun ; Krasnitz, Alexander ; Hicks, James ; Powers, R. Scott ; Stillman, Bruce

Understanding factors required for DNA replication will enrich our knowledge of this important process and potentially identify vulnerabilities that can be exploited in cancer therapy. We applied an assay that measures the stability of maintenance of an episomal plasmid in human tissue culture cells to screen for new DNA replication factors. We identify an important role for DDX5 in G1-to-S phase progression where it directly regulates DNA replication factor expression by promoting the [...]

Menée in vitro, cette étude met en évidence le double rôle joué par la protéine Beclin1, un élément de la voie de signalisation de l'autophagie, dans le développement d'une tumeur mammaire

Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells

Gong, C. ; Bauvy, C. ; Tonelli, G. ; Yue, W. ; Delomenie, C. ; Nicolas, V. ; Zhu, Y. ; Domergue, V. ; Marin-Esteban, V. ; Tharinger, H. ; Delbos, L. ; Gary-Gouy, H. ; Morel, A. P. ; Ghavami, S. ; Song, E. ; Codogno, P. ; Mehrpour, M.

Malignant breast tissue contains a rare population of multi-potent cells with the capacity to self-renew; these cells are known as cancer stem-like cells (CSCs) or tumor-initiating cells. Primitive mammary CSCs/progenitor cells can be propagated in culture as floating spherical colonies termed ‘mammospheres’. We show here that the expression of the autophagy protein Beclin 1 is higher in mammospheres established from human breast cancers or breast cancer cell lines (MCF-7 and BT474) than in the [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par une isoforme de la protéine p53 dans la régulation de l'angiogenèse de tumeurs de glioblastome

The p53 isoform, [Delta]133p53[alpha], stimulates angiogenesis and tumour progression

Bernard, H. ; Garmy-Susini, B. ; Ainaoui, N. ; Van Den Berghe, L. ; Peurichard, A. ; Javerzat, S. ; Bikfalvi, A. ; Lane, D. P. ; Bourdon, J. C. ; Prats, A. C.

The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53

Menée sur des échantillons de carcinomes du côlon et du sein, puis in vivo, cette étude met en évidence le rôle joué par une sous-unité de l'enzyme PI3K dans la progression tumorale

p85β phosphoinositide 3-kinase subunit regulates tumor progression

Cortés, Isabel ; Sánchez-Ruíz, Jesús ; Zuluaga, Susana ; Calvanese, Vincenzo ; Marqués, Miriam ; Hernández, Carmen ; Rivera, Teresa ; Kremer, Leonor ; González-García, Ana ; Carrera, Ana C.

PIK3R2 encodes a ubiquitous regulatory subunit (p85β) of PI3K, an enzyme that generates 3-polyphosphoinositides at the plasma membrane. PI3K activation triggers cell survival and migration. We found that p85β expression is elevated in breast and colon carcinomas and that its increased expression correlates with PI3K pathway activation and tumor progression. p85β expression induced moderate PIP3 generation at the cell membrane and enhanced cell invasion. In accordance, genetic alteration of [...]

Menée sur des échantillons tumoraux et des lignées cellulaires de cancer ovarien, cette étude suggère que la surexpression du micro-ARN 193b* induit une résistance au carboplatine

Genetic variation that predicts platinum sensitivity reveals the role of miR-193b* in chemotherapeutic susceptibility

Ziliak, Dana ; Gamazon, Eric R. ; LaCroix, Bonnie ; Im, Hae Kyung ; Wen, Yujia ; Huang, Rong Stephanie

Platinum agents are the backbone of cancer chemotherapy. Recently we identified and replicated the role of a single nucleotide polymorphism (SNP, rs1649942) in predicting platinum sensitivity both in vitro and in vivo. Using the CEU samples from the International HapMap Project, we found the same SNP to be a master regulator of multiple gene expression phenotypes, prompting us to investigate whether rs1649942-mediated regulation of microRNAs (miRNAs) may in part contribute to variation in [...]

Menée sur un modèle murin de cancer du pancréas, cette étude met en évidence, à partir du séquençage de l'ARN de cellules tumorales circulantes, le rôle joué par la signalisation Wnt dans le processus métastatique

RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis

Yu, Min ; Ting, David T. ; Stott, Shannon L. ; Wittner, Ben S. ; Ozsolak, Fatih ; Paul, Suchismita ; Ciciliano, Jordan C. ; Smas, Malgorzata E. ; Winokur, Daniel ; Gilman, Anna J. ; Ulman, Matthew J. ; Xega, Kristina ; Contino, Gianmarco ; Alagesan, Brinda ; Brannigan, Brian W. ; Milos, Patrice M. ; Ryan, David P. ; Sequist, Lecia V. ; Bardeesy, Nabeel ; Ramaswamy, Sridhar ; Toner, Mehmet ; Maheswaran, Shyamala ; Haber, Daniel A.

Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in CTCs. [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la kinase AXL dans l'apparition d'une résistance à l'erlotinib dans les cancers du poumon non à petites cellules présentant des mutations activatrices d'EGFR

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Zhang, Zhenfeng ; Lee, Jae Cheol ; Lin, Luping ; Olivas, Victor ; Au, Valerie ; Laframboise, Thomas ; Abdel-Rahman, Mohamed ; Wang, Xiaoqi ; Levine, Alan D. ; Rho, Jin Kyung ; Choi, Yun Jung ; Choi, Chang-Min ; Kim, Sang-We ; Jang, Se Jin ; Park, Young Soo ; Kim, Woo Sung ; Lee, Dae Ho ; Lee, Jung-Shin ; Miller, Vincent A. ; Arcila, Maria ; Ladanyi, Marc ; Moonsamy, Philicia ; Sawyers, Charles ; Boggon, Titus J. ; Ma, Patrick C. ; Costa, Carlota ; Taron, Miquel ; Rosell, Rafael ; Halmos, Balazs ; Bivona, Trever G.

Human non–small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in [...]

Cet article passe en revue les travaux récents sur le rôle du micro-ARN 155 dans la progression d'un cancer du sein

The Oncogenic Role of miR-155 in Breast Cancer

Mattiske, Sam ; Suetani, Rachel J ; Neilsen, Paul M ; Callen, David F

miR-155 is an oncogenic microRNA with well described roles in leukemia. However, additional roles of miR-155 in breast cancer progression have recently been described. A thorough literature search was conducted to review all published data to date examining the role of miR-155 in breast cancer. Data on all validated miR-155 target genes was collated to identify biological pathways relevant to miR-155 and breast cancer progression. Publications describing the clinical relevance, functional [...]

Cet article analyse les travaux récents sur le rôle de la transition mésenchymato-épithéliale dans le processus métastatique d'un cancer du sein

Mesenchymal–epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer

Gunasinghe, N. ; Wells, Alan ; Thompson, Erik ; Hugo, Honor

As yet, there is no cure for metastatic breast cancer. Historically, considerable research effort has been concentrated on understanding the processes of metastasis, how a primary tumour locally invades and systemically disseminates using the phenotypic switching mechanism of epithelial to mesenchymal transition (EMT); however, much less is understood about how metastases are then formed . Breast cancer metastases often look (and may even function) as ‘normal’ breast tissue, a bizarre [...]

Menée sur un modèle murin, cette étude montre la faisabilité d'une méthode de ciblage génétique pour fabriquer, à l'aide d'insertions d'éléments sur le génome, un modèle de carcinome hépatocellulaire

Induction of hepatocellular carcinoma by in vivo gene targeting

Wang, Pei-Rong ; Xu, Mei ; Toffanin, Sara ; Li, Yi ; Llovet, Josep M. ; Russell, David W.

The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting ∼1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300-kb chromosomal domain containing multiple mRNAs, snoRNAs, and microRNAs was activated surrounding the integration site. [...]

A partir de données portant sur une lignée cellulaire de cancer du sein et un échantillon de tumeur de la prostate, cette étude évalue la faisabilité d'une nouvelle méthode, appelée nFuse, pour identifier des réarrangements complexes du génome

nFuse: Discovery of complex genomic rearrangements in cancer using high-throughput sequencing

McPherson, Andrew William ; Wu, Chunxiao ; Wyatt, Alexander ; Shah, Sohrab P. ; Collins, Colin ; Sahinalp, S. Cenk

Complex Genomic Rearrangements (CGRs) are emerging as a new feature of cancer genomes. CGRs are characterized by multiple genomic breakpoints, and thus have the potential to simultaneously affect multiple genes, fusing some genes and interrupting other genes. Analysis of high-throughput whole genome shotgun sequencing (WGSS) is beginning to facilitate the discovery and characterization of CGRs, but further development of computational methods is required. We have developed an algorithmic method [...]