A partir de données portant sur 95 séquences du génome tumoral de divers types de cancer (sein, tête et cou, côlon-rectum, prostate, mélanome, myélome multiple et leucémie lymphocytaire chronique), cette étude identifie des facteurs génomiques associés à la distribution des réarrangements somatiques

Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability

Drier, Yotam ; Lawrence, Michael S ; Carter, Scott L ; Stewart, Chip ; Gabriel, Stacey B ; Lander, Eric S ; Meyerson, Matthew ; Beroukhim, Rameen ; Getz, Gad

Whole genome sequencing using massively parallel sequencing technologies enables accurate detection of somatic rearrangements in cancer. Pinpointing large numbers of rearrangement breakpoints to basepair resolution allows analysis of rearrangement microhomology and genomic location for every sample. Here we analyze 95 tumor genome sequences from breast, head and neck, colorectal, and prostate carcinomas and from melanoma, multiple myeloma and chronic lymphocytic leukemia. We discover three [...]

Menée sur 1 092 individus issus de 14 populations différentes, cette étude du projet 1 000 Genomes dresse une cartographie des variations génétiques au sein de ces populations

An integrated map of genetic variation from 1,092 human genomes

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million [...]

Menée sur 19 lignées cellulaires et trois paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un cancer du poumon, cette étude de séquençage de l'exome et du transcriptome met notamment en évidence de fréquentes mutations associées à l'épissage alternatif

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 ; N. 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 three 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 in vitro, cette étude met en évidence un mécanisme de régulation du suppresseur de tumeurs PTEN par la protéine PNUTS

PNUTS functions as a proto-oncogene by sequestering PTEN

Kavela, Sridhar ; Shinde, Swapnil R ; Ratheesh, Raman ; Viswakalyan, Kotapalli ; Bashyam, Murali D. ; Gowrishankar, Swarnalata ; Vamsy, Mohana ; Pattnaik, Sujith ; Rao, Subramanyeshwar ; Sastry, Regulagadda A. ; Srinivasulu, Mukta ; Chen, Junjie ; Maddika, Subbareddy

PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes such as survival, growth, motility, invasiveness and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN associated protein. PNUTS [...]

Menée in vitro, cette étude met en évidence un mécanisme de mort cellulaire par nécrose permettant de rendre compte de l'absence de cancers chez une espèce de rongeur, le rat taupe

Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism

Gorbunova, Vera ; Hine, Christopher ; Tian, Xiao ; Ablaeva, Julia ; Gudkov, Andrei V. ; Nevo, Eviatar ; Seluanov, Andrei

Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and resistance to cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for [...]

Menée sur des échantillons sanguins prélevés sur 85 patients atteints d'une leucémie myéloïde aiguë et 15 témoins, puis in vitro et in vivo, cette étude suggère que le micro-ARN 495 est un suppresseur de tumeurs et qu'il est sous-exprimé dans les leucémies myéloïdes aiguës avec réarrangements MLL

miR-495 is a tumor-suppressor microRNA down-regulated in MLL-rearranged leukemia

Jiang, Xi ; Huang, Hao ; Li, Zejuan ; He, Chunjiang ; Li, Yuanyuan ; Chen, Ping ; Gurbuxani, Sandeep ; Arnovitz, Stephen ; Hong, Gia-Ming ; Price, Colles ; Ren, Haomin ; Kunjamma, Rejani B. ; Neilly, Mary Beth ; Salat, Justin ; Wunderlich, Mark ; Slany, Robert K. ; Zhang, Yanming ; Larson, Richard A. ; Le Beau, Michelle M. ; Mulloy, James C. ; Rowley, Janet D. ; Chen, Jianjun

Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies with variable response to treatment. AMLs bearing MLL (mixed lineage leukemia) rearrangements are associated with intermediate or poor survival. MicroRNAs (miRNAs), a class of small noncoding RNAs, have been postulated to be important gene expression regulators virtually in all biological processes, including leukemogenesis. Through a large-scale, genome-wide miRNA expression profiling assay of 85 human AML and [...]

Menée à l'aide d'un modèle murin, cette étude montre qu'un polymorphisme à simple nucléotide identifié lors d'études d'association sur le génome entier, rs6983267, a un effet fonctionnel sur la tumorigenèse intestinale

Mice Lacking a Myc Enhancer That Includes Human SNP rs6983267 Are Resistant to Intestinal Tumors

Sur, Inderpreet Kaur ; Hallikas, Outi ; Vähärautio, Anna ; Yan, Jian ; Turunen, Mikko ; Enge, Martin ; Taipale, Minna ; Karhu, Auli ; Aaltonen, Lauri A. ; Taipale, Jussi

Multiple cancer-associated single nucleotide polymorphisms (SNPs) have been mapped to conserved sequences within a 500-kilobase region upstream of the MYC oncogene on human chromosome 8q24. These SNPs may affect cancer development through altered regulation of MYC expression, but this hypothesis has been difficult to confirm. We generated mice deficient in Myc-335, a putative MYC regulatory element that contains rs6983267, a SNP accounting for more human cancer-related morbidity than any other [...]

Menée sur des lignées cellulaires et des échantillons tumoraux, cette étude suggère que, par contraste avec de précédents résultats, CDX2 ne joue pas un rôle de suppresseur de tumeurs mais bien d'oncogène dans le cancer colorectal

CDX2 is an amplified lineage-survival oncogene in colorectal cancer

Salari, Keyan ; Spulak, Mary E. ; Cuff, Justin ; Forster, Andrew D. ; Giacomini, Craig P. ; Huang, Stephanie ; Ko, Melissa E. ; Lin, Albert Y. ; van de Rijn, Matt ; Pollack, Jonathan R.

The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, “lineage-survival” oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, [...]

Menée in vitro, cette étude met en évidence le rôle joué par une protéine Trithorax, MLL, dans les cellules souches de glioblastome

A Tumorigenic MLL-Homeobox Network in Human Glioblastoma Stem Cells

Gallo, Marco ; Ho, Jenny ; Coutinho, Fiona ; Vanner, Robert ; Lee, Lilian ; Head, Renee ; Ling, Erick ; Clarke, Ian ; Dirks, Peter

Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behavior are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here we provide the first mechanistic insights into the role of the Trithorax protein MLL in maintaining cancer stem cell characteristics in human glioblastoma. We found that MLL directly activates the Homeobox [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du facteur induit par l'hypoxie HIF-1, l'histone déméthylase JMJD2C favorise la croissance d'une tumeur mammaire et la formation de métastases pulmonaires

Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression

Luo, Weibo ; Chang, Ryan ; Zhong, Jun ; Pandey, Akhilesh ; Semenza, Gregg L.

Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that play key roles in breast cancer biology. We hypothesized that interaction of HIF-1 with epigenetic regulators may increase HIF-1 transcriptional activity, and thereby promote breast cancer progression. We report that the histone demethylase jumonji domain containing protein 2C (JMJD2C) selectively interacts with HIF-1α, but not HIF-2α, and that HIF-1α mediates recruitment of JMJD2C to the hypoxia response [...]

Menée in vitro, cette étude met en évidence le rôle joué par une isoforme d'une protéine du cytosquelette, hMENA, dans la progression d'un cancer du sein

Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors

Di Modugno, Francesca ; Iapicca, Pierluigi ; Boudreau, Aaron ; Mottolese, Marcella ; Terrenato, Irene ; Perracchio, Letizia ; Carstens, Russ P. ; Santoni, Angela ; Bissell, Mina J. ; Nisticò, Paola

Human mena (hMENA), a member of the actin cytoskeleton regulators Ena/VASP, is overexpressed in high-risk preneoplastic lesions and in primary breast tumors and has been identified as playing a role in invasiveness and poor prognosis in breast cancers that express HER2. Here we identify a unique isoform, hMENAΔv6, derived from the hMENA alternative splicing program. In an isogenic model of human breast cancer progression, we show that hMENA11a is expressed in premalignant cells, whereas [...]

Cet article passe en revue les travaux récents sur l’intérêt de la modélisation numérique dans divers domaines médicaux, dont le cancer

Computational Medicine: Translating Models to Clinical Care

Winslow, Raimond L. ; Trayanova, Natalia ; Geman, Donald ; Miller, Michael I.

Because of the inherent complexity of coupled nonlinear biological systems, the development of computational models is necessary for achieving a quantitative understanding of their structure and function in health and disease. Statistical learning is applied to high-dimensional biomolecular data to create models that describe relationships between molecules and networks. Multiscale modeling links networks to cells, organs, and organ systems. Computational approaches are used to characterize [...]