Menée sur un échantillon métastatique prélevé sur un patient atteint d'un mélanome présentant la mutation BRAF-V600E et ayant été traité pendant sept mois à l'aide de vemurafenib, cette étude met en évidence une hétérogénéité moléculaire dans cette métastase

Intratumoral molecular heterogeneity in a BRAF-mutant, BRAF inhibitor-resistant melanoma: a case illustrating the challenges for personalized medicine

Wilmott, James Samuel ; Tembe, Varsha ; Howle, Julie R ; Sharma, Raghwa ; Thompson, John F. ; Rizos, Helen ; Lo, Roger S. ; Kefford, Richard F. ; Scolyer, Richard A ; Long, Georgina V.

Targeted therapies are increasingly being used to treat a variety of cancers. Their efficacy depends upon the accurate detection and targeting of a specific mutation or aberration in the tumour. All cancers such as melanoma are molecularly heterogeneous, with drug resistant subclones present prior to treatment or emerging as a result of targeted therapies. Here we show intra-lesional molecular heterogeneity in a progressing V600E BRAF-mutant melanoma metastasis from a patient treated for 7 [...]

Menée sur deux patients atteints d'un paragangliome avec polycythémie, cette étude met en évidence des mutations du gène codant pour le facteur

Somatic HIF2A Gain-of-Function Mutations in Paraganglioma with Polycythemia

Zhuang, Zhengping ; Yang, Chunzhang ; Lorenzo, Felipe ; Merino, Maria ; Fojo, Tito ; Kebebew, Electron ; Popovic, Vera ; Stratakis, Constantine A. ; Prchal, Josef T. ; Pacak, Karel

Hypoxia-inducible factors are transcription factors controlling energy, iron metabolism, erythropoiesis, and development. When these proteins are dysregulated, they contribute to tumorigenesis and cancer progression. However, mutations in genes encoding

Menée sur 178 cas de carcinomes épidermoïdes du poumon dans le cadre du projet "The Cancer Genome Atlas", cette étude analyse le spectre des altérations génomiques et épigénomiques et identifie notamment des mutations récurrentes dans 11 gènes

Comprehensive genomic characterization of squamous cell lung cancers

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is [...]

Menée à l'aide d'une biopuce destinée à analyser 548 fusions de gènes, cette étude confirme, sur 27 échantillons de tumeurs de la thyroïde et 3 lignées cellulaires, le rôle pathogénique joué par les fusions de gènes RET/PTC1, RET/PTC3 et PAX8-PPARG

Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes

Celestino, Ricardo ; Sigstad, Eva ; Løvf, Marthe ; Thomassen, Gard O. S. ; Grøholt, Krystyna K. ; Jørgensen, Lars H. ; Berner, Aasmund ; Castro, Patrícia ; Lothe, Ragnhild A. ; Bjøro, Trine ; Sobrinho-Simões, Manuel ; Soares, Paula ; Skotheim, Rolf I.

Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8-PPARG fusion is present in the neoplastic lesions that have a follicular architecture—follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to [...]

Cet article passe en revue les travaux récents sur les mécanismes associés à l'état de la chromatine et aux voies de réponse aux dommages à l'ADN dans le cancer

Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer

Sulli, Gabriele ; Di Micco, Raffaella ; di Fagagna, Fabrizio d'Adda

The generation of DNA lesions and the resulting activation of DNA damage response (DDR) pathways are both affected by the chromatin status at the site of damaged DNA. In turn, DDR activation affects the chromatin at both the damaged site and across the whole genome. Cellular senescence and cancer are associated with the engagement of the DDR pathways and with profound chromatin changes. In this Opinion article, we discuss the interplay between chromatin and DDR factors in the context of [...]

Menée in vitro, cette étude met en évidence une interdépendance de la réponse au cisplatine de p53 dans les cellules cancéreuses et des fibroblastes associés au cancer dans le mircoenvironnement tumoral

Cancer cells cue the p53 response of cancer-associated fibroblasts (CAFs) to cisplatin

Schmid, Jens O ; Dong, Meng ; Haubeiss, Silke ; Friedel, Godehard ; Bode, Sabine ; Grabner, Andreas ; Ott, German ; Mürdter, Thomas E ; Oren, Moshe ; Aulitzky, Walter E ; van der Kuip, Heiko

Current understanding of the p53 response is based mainly upon in vitro studies of homogeneous cell populations. However, there is little information on whether the same principles operate within heterogeneous tumor tissues that are comprised of cancer cells and other cell types, including cancer-associated fibroblasts (CAFs). Using ex-vivo tissue cultures, we investigated p53 status and responses to cisplatin in tumor cells and CAFs from tissue specimens isolated from 32 lung cancer patients. [...]

Cet article passe en revue les travaux récents sur le rôle du facteur de croissance transformant TGF-bêta dans les tumeurs solides et les hémopathies malignes

TGF-beta -- an excellent servant but a bad master

Kubiczkova, Lenka ; Sedlarikova, Lenka ; Hajek, Roman ; Sevcikova, Sabina

The transforming growth factor (TGF-beta) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-beta signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding [...]

Menée sur 280 échantillons prélevés sur des patients atteints d'une leucémie lymphoblastique aiguë T, cette étude française met en évidence des mécanismes d'activation des oncogènes liés à des translocations chromosomiques impliquant des loci du récepteur TCR

Extensive molecular mapping of TCRα/δ and TCRβ involved chromosomal translocations reveals distinct mechanisms of oncogenes activation in T-ALL

Le Noir, Sandrine ; Ben Abdelali, Raouf ; Lelorch, Marc ; Bergeron, Julie ; Sungalee, Stephanie ; Payet-Bornet, Dominique ; Villarèse, Patrick ; Petit, Arnaud ; Callens, Celine ; Lhermitte, Ludovic ; Baranger, Laurence ; Radford-weiss, Isabelle ; Grégoire, Marie-Josée ; Dombret, Hervé ; Ifrah, Norbert ; Spicuglia, Salvatore ; Romana, Serge ; Soulier, Jean ; Nadel, Bertrand ; Macintyre, Elizabeth ; Asnafi, Vahid

Chromosomal translocations involving the T Cell Receptor (TCR) loci represent one of the most recurrent oncogenic hallmarks of T-cell acute lymphoblastic leukaemia (T-ALL) and are generally believed to result from illegitimate V(D)J recombination events. However, molecular characterization and evaluation of the extent of recombinase involvement at the TCR-oncogene junction has not been fully evaluated. Screening for TCRβ and TCRα/δ translocations by FISH and LM-PCR in 280 T-ALLs allowed [...]

Menée sur des échantillons prélevés sur des patients atteints d'une leucémie et à l'aide d'un modèle murin, cette étude met en évidence des gènes impliqués dans la régulation de la croissance et de la survie des cellules souches leucémiques

Gene Sets Identified with Oncogene Cooperativity Analysis Regulate In Vivo Growth and Survival of Leukemia Stem Cells

Ashton, John M ; Balys, Marlene ; Neering, Sarah J ; Hassane, Duane C ; Cowley, Glenn ; Root, David E ; Miller, Peter G ; Ebert, Benjamin L ; McMurray, Helene R ; Land, Hartmut ; Jordan, Craig T

Leukemia stem cells (LSCs) represent a biologically distinct subpopulation of myeloid leukemias, with reduced cell cycle activity and increased resistance to therapeutic challenge. To better characterize key properties of LSCs, we employed a strategy based on identification of genes synergistically dysregulated by cooperating oncogenes. We hypothesized that such genes, termed cooperation response genes (CRGs), would represent regulators of LSC growth and survival. Using both a primary mouse [...]

Meée sur un modèle murin, des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'une tumeur maligne des gaines des nerfs périphériques, cette étude met en évidence un mécanisme par lequel, en activant le facteur de choc thermique HSF1, la perte du gène suppresseur de tumeurs NF1 favorise la cancérogenèse

Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis

Dai, Chengkai ; Santagata, Sandro ; Tang, Zijian ; Shi, Jiayuan ; Cao, Junxia ; Kwon, Hyoungtae ; Bronson, Roderick T. ; Whitesell, Luke ; Lindquist, Susan

Intrinsic stress response pathways are frequently mobilized within tumor cells. The mediators of these adaptive mechanisms and how they contribute to carcinogenesis remain poorly understood. A striking example is heat shock factor 1 (HSF1), master transcriptional regulator of the heat shock response. Surprisingly, we found that loss of the tumor suppressor gene neurofibromatosis type 1 (Nf1) increased HSF1 levels and triggered its activation in mouse embryonic fibroblasts. As a consequence, [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en stimulant les fibroblastes associés au cancer dans le microenvironnement, l'expression du gène HOXA9 dans les cellules d'un cancer épithélial ovarien favorise la croissance tumorale

HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts

Ko, Song Yi ; Barengo, Nicolas ; Ladanyi, Andras ; Lee, Ju-Seog ; Marini, Frank ; Lengyel, Ernst ; Naora, Honami

Epithelial ovarian cancers (EOCs) often exhibit morphologic features of embryonic Müllerian duct–derived tissue lineages and colonize peritoneal surfaces that overlie connective and adipose tissues. However, the mechanisms that enable EOC cells to readily adapt to the peritoneal environment are poorly understood. In this study, we show that expression of HOXA9, a Müllerian-patterning gene, is strongly associated with poor outcomes in patients with EOC and in mouse xenograft models of EOC. [...]

Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un gliome, avec et sans mutation des gènes IDH1 et IDH2, et sur des données issues du projet "The Cancer Genome Atlas", cette étude identifie une fréquente hyperméthylation du site promoteur du gène RBP1, impliqué dans la synthèse de l'acide rétinoïque

Identification of Retinol Binding Protein 1 Promoter Hypermethylation in Isocitrate Dehydrogenase 1 and 2 Mutant Gliomas

Chou, Arthur P. ; Chowdhury, Reshmi ; Li, Sichen ; Chen, Weidong ; Kim, Andrew J. ; Piccioni, David E. ; Selfridge, Julia M. ; Mody, Reema R. ; Chang, Stephen ; Lalezari, Shadi ; Lin, Jeffrey ; Sanchez, Desiree E. ; Wilson, Ryan W. ; Garrett, Matthew C. ; Harry, Bret ; Mottahedeh, Jack ; Nghiemphu, Phioanh L. ; Kornblum, Harley I. ; Mischel, Paul S. ; Prins, Robert M. ; Yong, William H. ; Cloughesy, Timothy ; Nelson, Stanley F. ; Liau, Linda M. ; Lai, Albert

Background Mutations in isocitrate dehydrogenase 1 (IDH1) and associated CpG island hypermethylation represent early events in the development of low-grade gliomas and secondary glioblastomas. To identify candidate tumor suppressor genes whose promoter methylation may contribute to gliomagenesis, we compared methylation profiles of IDH1 mutant (MUT) and IDH1 wild-type (WT) tumors using massively parallel reduced representation bisulfite sequencing.Methods Reduced representation bisulfite [...]

Menée in vitro, in vivo et sur 499 échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude montre que l'absence de la protéine p63 et de son micro-ARN cible (miR-205) favorise le processus métastatique

Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer

Tucci, Paola ; Agostini, Massimiliano ; Grespi, Francesca ; Markert, Elke K. ; Terrinoni, Alessandro ; Vousden, Karen H. ; Muller, Patricia A. J. ; Dötsch, Volker ; Kehrloesser, Sebastian ; Sayan, Berna S. ; Giaccone, Giuseppe ; Lowe, Scott W. ; Takahashi, Nozomi ; Vandenabeele, Peter ; Knight, Richard A. ; Levine, Arnold J. ; Melino, Gerry

p63 inhibits metastasis. Here, we show that p63 (both TAp63 and ΔNp63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial–mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti–miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing [...]