A partir d'échantillons de tissu tumoral et de tissu sain prélevés sur 5 473 patients atteints d'un cancer, cette étude met en évidence une fréquente perte d'expression de deux petits ARNs nucléolaires, puis montre que, dans les tumeurs présentant un gène KRAS muté, cette perte d'expression favorise la tumorigenèse

The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer

Siprashvili, Zurab ; Webster, Dan E. ; Johnston, Danielle ; Shenoy, Rajani M. ; Ungewickell, Alexander J. ; Bhaduri, Aparna ; Flockhart, Ross ; Zarnegar, Brian J. ; Che, Yonglu ; Meschi, Francesca ; Puglisi, Joseph D. ; Khavari, Paul A.

Small nucleolar RNAs (snoRNAs) are conserved noncoding RNAs best studied as ribonucleoprotein (RNP) guides in RNA modification. To explore their role in cancer, we compared 5,473 tumor-normal genome pairs to identify snoRNAs with frequent copy number loss. The SNORD50A-SNORD50B snoRNA locus was deleted in 10–40% of 12 common cancers, where its loss was associated with reduced survival. A human protein microarray screen identified direct SNORD50A and SNORD50B RNA binding to K-Ras. Loss of [...]

A partir de données portant sur 11 119 tumeurs (41 types de cancer), cette étude identifie 470 hotspots mutationnels dans 275 gènes

Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity

Chang, Matthew T. ; Asthana, Saurabh ; Gao, Sizhi Paul ; Lee, Byron H. ; Chapman, Jocelyn S. ; Kandoth, Cyriac ; Gao, JianJiong ; Socci, Nicholas D. ; Solit, David B. ; Olshen, Adam B. ; Schultz, Nikolaus ; Taylor, Barry S.

Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized. An approach to detect significantly mutated residues, rather than methods that identify recurrently mutated genes, may uncover new biologically and therapeutically relevant driver mutations. Here, we developed a statistical algorithm to identify recurrently mutated residues in tumor samples. We applied the algorithm to 11,119 [...]

A partir de données portant sur 1 165 exomes issus du projet "The Cancer Genome Atlas" (12 types de cancer), cette étude analyse la profondeur de l'hétérogénéité intratumorale et évalue l'association entre le nombre de populations clonales et la mortalité

Pan-cancer analysis of the extent and consequences of intratumor heterogeneity

Andor, Noemi ; Graham, Trevor A. ; Jansen, Marnix ; Xia, Li C. ; Aktipis, C. Athena ; Petritsch, Claudia ; Ji, Hanlee P. ; Maley, Carlo C.

Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a [ge]10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, [rho] [...]

Menée sur 14 patients atteints d'un lymphome diffus à grandes cellules B réfractaire/récidivant, cette étude française de séquençage de l'exome entier identifie un ensemble de mutations somatiques, notamment dans des gènes de la voie de signalisation NF-kappaB

Whole exome sequencing of relapsed/refractory patients expands the repertoire of somatic mutations in diffuse large B-cell lymphoma

Mareschal, Sylvain ; Dubois, Sydney ; Viailly, Pierre-Julien ; Bertrand, Philippe ; Bohers, Elodie ; Maingonnat, Catherine ; Jais, Jean-Philippe ; Tesson, Bruno ; Ruminy, Philippe ; Peyrouze, Pauline ; Copie-Bergman, Christiane ; Fest, Thierry ; Jo Molina, Thierry ; Haioun, Corinne ; Salles, Gilles ; Tilly, Herve ; Lecroq, Thierry ; Leroy, Karen ; Jardin, Fabrice

Despite the many efforts already spent to enumerate somatic mutations in diffuse large B-cell lymphoma (DLBCL), previous whole-genome and whole-exome studies conducted on patients of mixed outcomes failed at characterizing the 30% of patients who will relapse or resist current immunochemotherapies. To address this issue, we performed whole-exome sequencing of normal/tumoral DNA pairs in 14 relapsed/refractory (R/R) patients subclassified by full-transcriptome arrays (six activated B-cell like, [...]

A partir d'échantillons tumoraux prélevés sur 13 patients atteints d'un carcinome épidermoïde de la tête et du cou présentant des métastases synchrones dans les ganglions lymphatiques et sur 13 patients présentant des tumeurs métachrones récidivantes, cette étude de séquençage de l'exome entier analyse le degré de concordance entre les mutations observées dans les tumeurs appariées

Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Hedberg, Matthew L. ; Goh, Gerald ; Chiosea, Simion I. ; Bauman, Julie E. ; Freilino, Maria L. ; Zeng, Yan ; Wang, Lin ; Diergaarde, Brenda B. ; Gooding, William E. ; Lui, Vivian W. Y. ; Herbst, Roy S. ; Lifton, Richard P. ; Grandis, Jennifer R.

BACKGROUND. Recurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC. METHODS. Whole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients [...]

Menée in vivo, cette étude met en évidence le rôle joué par les kinases de la famille RAF, ainsi que les kinases MERTK et NTRK2, dans le processus métastatique d'un cancer de la prostate résistant à la castration

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Faltermeier, Claire M. ; Drake, Justin M. ; Clark, Peter M. ; Smith, Bryan A. ; Zong, Yang ; Volpe, Carmen ; Mathis, Colleen ; Morrissey, Colm ; Castor, Brandon ; Huang, Jiaoti ; Witte, Owen N.

Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes de nature épigénétique par lesquels MLL5 et H3.3 interagissent pour favoriser le renouvellement des cellules souches de glioblastome chez l'adulte

MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin

Gallo, Marco ; Coutinho, Fiona J ; Vanner, Robert J ; Gayden, Tenzin ; Mack, Stephen C ; Murison, Alex ; Remke, Marc ; Li, Ren ; Takayama, Naoya ; Desai, Kinjal ; Lee, Lilian ; Lan, Xiaoyang ; Park, Nicole I ; Barsyte-Lovejoy, Dalia ; Smil, David ; Sturm, Dominik ; Kushida, Michelle M ; Head, Renee ; Cusimano, Michael D ; Bernstein, Mark ; Clarke, Ian D ; Dick, John E ; Pfister, Stefan M ; Rich, Jeremy N ; Arrowsmith, Cheryl H ; Taylor, Michael D ; Jabado, Nada ; Bazett-Jones, David P ; Lupien, Mathieu ; Dirks, Peter B

Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing [...]

Cet article passe en revue les études précliniques récentes mettant en évidence le rôle joué par la perte d'expression de PTEN dans les leucémies lymphoblastiques aiguës T et les lymphomes T

Oncogenic PTEN functions and models in T-cell malignancies

Tesio, M. ; Trinquand, A. ; Macintyre, E. ; Asnafi, V.

PTEN is a protein phosphatase that is crucial to prevent the malignant transformation of T-cells. Although a numerous mechanisms regulate its expression and function, they are often altered in T-cell acute lymphoblastic leukaemias and T-cell lymphomas. As such, PTEN inactivation frequently occurs in these malignancies, where it can be associated with chemotherapy resistance and poor prognosis. Different Pten knockout models recapitulated the development of T-cell leukaemia/lymphoma, [...]