A partir de l'analyse de colonies dérivées de cellules uniques prélevées en série sur 28 patients atteints d'une leucémie myélomonocytaire chronique, cette étude met en évidence une dominance clonale apparaissant de façon précoce dans l'évolution de la maladie

Clonal architecture of chronic myelomonocytic leukemias

Itzykson, Raphaël ; Kosmider, Olivier ; Renneville, Aline ; Morabito, Margot ; Preudhomme, Claude ; Berthon, Céline ; Adès, Lionel ; Fenaux, Pierre ; Platzbecker, Uwe ; Gagey, Olivier ; Rameau, Philippe ; Meurice, Guillaume ; Oréar, Cédric ; Delhommeau, François ; Bernard, Olivier A. ; Fontenay, Michaela ; Vainchenker, William ; Droin, Nathalie ; Solary, Eric

Genomic studies in chronic myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MPN/MDS, have identified common mutations in genes encoding signaling, epigenetic, transcription and splicing factors. In the present study, we interrogated the clonal architecture by mutation-specific discrimination analysis of single-cell-derived colonies in 28 patients with chronic myelomonocytic leukemias (CMML), the most frequent MPN/MDS. This analysis reveals [...]

Menée sur 124 cas, cette étude dresse le paysage génomique des leucémies lymphoblastiques aiguës hypodiploïdes

The genomic landscape of hypodiploid acute lymphoblastic leukemia

Holmfeldt, Linda ; Wei, Lei ; Diaz-Flores, Ernesto ; Walsh, Michael ; Zhang, Jinghui ; Ding, Li ; Payne-Turner, Debbie ; Churchman, Michelle ; Andersson, Anna ; Chen, Shann-Ching ; McCastlain, Kelly ; Becksfort, Jared ; Ma, Jing ; Wu, Gang ; Patel, Samir N. ; Heatley, Susan L. ; Phillips, Letha A. ; Song, Guangchun ; Easton, John ; Parker, Matthew ; Chen, Xiang ; Rusch, Michael ; Boggs, Kristy ; Vadodaria, Bhavin ; Hedlund, Erin ; Drenberg, Christina ; Baker, Sharyn ; Pei, Deqing ; Cheng, Cheng ; Huether, Robert ; Lu, Charles ; Fulton, Robert S. ; Fulton, Lucinda L. ; Tabib, Yashodhan ; Dooling, David J. ; Ochoa, Kerri ; Minden, Mark ; Lewis, Ian D. ; To, L. Bik ; Marlton, Paula ; Roberts, Andrew W. ; Raca, Gordana ; Stock, Wendy ; Neale, Geoffrey ; Drexler, Hans G. ; Dickins, Ross A. ; Ellison, David W. ; Shurtleff, Sheila A. ; Pui, Ching-Hon ; Ribeiro, Raul C. ; Devidas, Meenakshi ; Carroll, Andrew J. ; Heerema, Nyla A. ; Wood, Brent ; Borowitz, Michael J. ; Gastier-Foster, Julie M. ; Raimondi, Susana C. ; Mardis, Elaine R. ; Wilson, Richard K. ; Downing, James R. ; Hunger, Stephen P. ; Loh, Mignon L. ; Mullighan, Charles G.

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras [...]

A partir de 18 échantillons tumoraux prélevés sur des patients atteints d'un mélanome de l'uvée, cette étude identifie la présence de mutations localisées exclusivement sur le codon 625 du gène SF3B1

Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma

Harbour, J. William ; Roberson, Elisha D. O. ; Anbunathan, Hima ; Onken, Michael D. ; Worley, Lori A. ; Bowcock, Anne M.

Uveal melanoma is the most common primary cancer of the eye and often results in fatal metastasis. Here, we describe mutations occurring exclusively at codon 625 of the SF3B1 gene, encoding splicing factor 3B subunit 1, in low-grade uveal melanomas with good prognosis. Thus, uveal melanoma is among a small group of cancers associated with SF3B1 mutations, and these mutations denote a distinct molecular subset of uveal melanomas.

Menée sur des lignées cellulaires de cancer colorectal, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du gène NOTCH, une amplification du gène LNX2 induit une activation aberrante de la voie de signalisation WNT/β-caténine

Genetic amplication of the NOTCH modulator LNX2 upregulates the WNT/β-catenin pathway in colorectal cancer

Camps, Jordi ; Pitt, Jason J ; Emons, Georg ; Hummon, Amanda B ; Case, Chanelle M. ; Grade, Marian ; Jones, Tamara L ; Nguyen, Quang T ; Ghadimi, B. Michael ; Beissbarth, Tim ; Difilippantonio, Michael J. ; Caplen, Natasha J ; Ried, Thomas

Chromosomal copy number alterations (aneuploidy) define the genomic landscape of most cancer cells, but identification of the oncogenic drivers behind these imbalances remains an unfinished task. In this study, we conducted a systematic analysis of colorectal carcinomas that integrated genomic copy number changes and gene expression profiles. This analysis revealed 44 highly overexpressed genes mapping to localized amplicons on chromosome 13, gains of which occur often in colorectal cancers. [...]

Menée sur 240 cas, cette étude met en évidence l'éventail des mutations somatiques associées aux neuroblastomes à haut risque

The genetic landscape of high-risk neuroblastoma

Pugh, Trevor J. ; Morozova, Olena ; Attiyeh, Edward F. ; Asgharzadeh, Shahab ; Wei, Jun S. ; Auclair, Daniel ; Carter, Scott L. ; Cibulskis, Kristian ; Hanna, Megan ; Kiezun, Adam ; Kim, Jaegil ; Lawrence, Michael S. ; Lichenstein, Lee ; McKenna, Aaron ; Pedamallu, Chandra Sekhar ; Ramos, Alex H. ; Shefler, Erica ; Sivachenko, Andrey ; Sougnez, Carrie ; Stewart, Chip ; Ally, Adrian ; Birol, Inanc ; Chiu, Readman ; Corbett, Richard D. ; Hirst, Martin ; Jackman, Shaun D. ; Kamoh, Baljit ; Khodabakshi, Alireza Hadj ; Krzywinski, Martin ; Lo, Allan ; Moore, Richard A. ; Mungall, Karen L. ; Qian, Jenny ; Tam, Angela ; Thiessen, Nina ; Zhao, Yongjun ; Cole, Kristina A. ; Diamond, Maura ; Diskin, Sharon J. ; Mosse, Yael P. ; Wood, Andrew C. ; Ji, Lingyun ; Sposto, Richard ; Badgett, Thomas ; London, Wendy B. ; Moyer, Yvonne ; Gastier-Foster, Julie M. ; Smith, Malcolm A. ; Auvil, Jaime M. Guidry ; Gerhard, Daniela S. ; Hogarty, Michael D. ; Jones, Steven J. M. ; Lander, Eric S. ; Gabriel, Stacey B. ; Getz, Gad ; Seeger, Robert C. ; Khan, Javed ; Marra, Marco A. ; Meyerson, Matthew ; Maris, John M.

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median [...]

Menée sur 65 échantillons tumoraux prélevés sur des patients atteints d'un méningiome, cette étude identifie la présence de mutations des gènes AKT1 et SMO dans un sous-groupe de tumeurs ne présentant pas d'altérations du gène NF2

Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

Brastianos, Priscilla K. ; Horowitz, Peleg M. ; Santagata, Sandro ; Jones, Robert T. ; McKenna, Aaron ; Getz, Gad ; Ligon, Keith L. ; Palescandolo, Emanuele ; Van Hummelen, Paul ; Ducar, Matthew D. ; Raza, Alina ; Sunkavalli, Ashwini ; MacConaill, Laura E. ; Stemmer-Rachamimov, Anat O. ; Louis, David N. ; Hahn, William C. ; Dunn, Ian F. ; Beroukhim, Rameen

Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of all meningiomas1, but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas had simple genomes, with fewer mutations, rearrangements and copy-number alterations than reported in [...]

Menée à l'aide de lignées cellulaires de divers types de cancer, à l'aide de xénogreffes et d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer de l'ovaire, cette étude met en évidence un mécanisme par lequel, en régulant négativement l'expression de p53, le gène RNF2 codant pour une E3 ligase favorise la croissance tumorale

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

Su, Wen-jing ; Fang, Jun-shun ; Cheng, Feng ; Liu, Chao ; Zhou, Fang ; Zhang, Jian

Large numbers of studies have focused on the posttranslational regulation of p53 activity. One of the best-known negative regulators for p53 is MDM2, an E3 ubiquitin ligase that promotes p53 degradation through proteasome degradation pathways. Additional E3 ligases have also been reported to negatively regulate p53. However, whether these E3 ligases have distinct/overlapping roles in the regulation of p53 is largely unknown. In this study, we identify RNF2 (ring finger protein 2) as an E3 [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le gène Phactr4 joue un rôle de suppresseur de tumeurs dans divers types de cancer

STOP gene Phactr4 is a tumor suppressor

Solimini, Nicole L. ; Liang, Anthony C. ; Xu, Chunxiao ; Pavlova, Natalya N. ; Xu, Qikai ; Davoli, Teresa ; Li, Mamie Z. ; Wong, Kwok-Kin ; Elledge, Stephen J.

Cancer develops through genetic and epigenetic alterations that allow unrestrained proliferation and increased survival. Using a genetic RNAi screen, we previously identified hundreds of suppressors of tumorigenesis and/or proliferation (STOP) genes that restrain normal cell proliferation. Our STOP gene set was significantly enriched for known and putative tumor suppressor genes. Here, we report a tumor-suppressive role for one STOP gene, phosphatase and actin regulator 4 (PHACTR4). Phactr4 is [...]

Menée à l'aide d'outils de séquençage de prochaine génération sur des échantillons prélevés sur des patients atteints d'un endobrachyœsophage ayant progressé en un adénocarcinome, puis sur des lignées cellulaires, cette étude met en évidence le rôle de suppresseur de tumeurs joué par le gène ARID1A dans ce processus

Next-generation sequencing of endoscopic biopsies identifies ARID1A as a tumor-suppressor gene in Barrett's esophagus

Streppel, M. M. ; Lata, S. ; DelaBastide, M. ; Montgomery, E. A. ; Wang, J. S. ; Canto, M. I. ; Macgregor-Das, A. M. ; Pai, S. ; Morsink, F. H. M. ; Offerhaus, G. J. ; Antoniou, E. ; Maitra, A. ; McCombie, W. R.

The incidence of Barrett’s esophagus (BE)-associated esophageal adenocarcinoma (EAC) is increasing. Next-generation sequencing (NGS) provides an unprecedented opportunity to uncover genomic alterations during BE pathogenesis and progression to EAC, but treatment-naive surgical specimens are scarce. The objective of this study was to establish the feasibility of using widely available endoscopic mucosal biopsies for successful NGS, using samples obtained from a BE ‘progressor’. Paired-end [...]

Menée sur des lignées cellulaires d'adénocarcinome du poumon présentant une amplification du gène NKX2-1, cette étude identifie le rôle joué par l'expression du gène LMO3 dans la survie des cellules cancéreuses

Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target

Watanabe, Hideo ; Francis, Joshua M. ; Woo, Michele S. ; Etemad, Banafsheh ; Lin, Wenchu ; Fries, Daniel F. ; Peng, Shouyong ; Snyder, Eric L. ; Tata, Purushothama Rao ; Izzo, Francesca ; Schinzel, Anna C. ; Cho, Jeonghee ; Hammerman, Peter S. ; Verhaak, Roel G. ; Hahn, William C. ; Rajagopal, Jayaraj ; Jacks, Tyler ; Meyerson, Matthew

The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To study the transcriptional impact of NKX2-1 amplification, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma and analyzed DNA-binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation. Integration of these expression and cistromic analyses identified LMO3, itself encoding a transcription [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par l'activation du gène MLK4, en coopération avec la signalisation RAS, dans le développement d'un cancer colorectal

Mixed lineage kinase MLK4 is activated in colorectal cancers where it synergistically cooperates with activated RAS signaling in driving tumorigenesis

Martini, Miriam ; Russo, Mariangela ; Lamba, Simona ; Vitiello, Elisa ; Crowley, Emily H. ; Sassi, Francesco ; Romanelli, Davide ; Frattini, Milo ; Marchetti, Antonio ; Bardelli, Alberto

Colorectal cancers are commonly classified into those with microsatellite instability (MSI) and those that are microsatellite stable (MSS) but chromosomally unstable. The latter are characterized by poor prognosis and remain largely intractable at the metastatic stage. Comprehensive mutational analyses have revealed that the Mixed Lineage Kinase 4 (MLK4) protein kinase is frequently mutated in MSS CRC with ~50% of the mutations occurring in KRAS or BRAF mutant tumors. This kinase has not been [...]

Menée à partir d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome rénal à cellules claires, puis in vitro et in vivo, cette étude suggère que le gène LKB1 joue un rôle de suppresseur de tumeurs

Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo

Duivenvoorden, W. C. ; Beatty, L. K. ; Lhotak, S. ; Hill, B. ; Mak, I. ; Paulin, G. ; Gallino, D. ; Popovic, S. ; Austin, R. C. ; Pinthus, J. H.

Background: Evidence suggests that dysregulation of energy-sensing pathways closely associates with renal cell carcinoma (RCC) development. The metabolic regulation is largely controlled by 5′-AMP activated protein kinase (AMPK) which is activated through phosphorylation by LKB1. Methods: The expression of LKB1 was determined by reverse transcription–PCR using 10 clinical clear cell RCC (ccRCC) samples and their adjacent normal renal parenchyma, and by immunohistochemical staining of two tissue [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par les voies de signalisation TRB3 et MAPK-ERK/TGFβ dans la régulation du gène Notch, dont l'activation est associée à un pronostic défavorable dans le cancer du sein

High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer

Izrailit, Julia ; Berman, Hal K. ; Datti, Alessandro ; Wrana, Jeffrey L. ; Reedijk, Michael

Expression of the Notch ligand Jagged 1 (JAG1) and Notch activation promote poor-prognosis in breast cancer. We used high throughput screens to identify elements responsible for Notch activation in this context. Chemical kinase inhibitor and kinase-specific small interfering RNA libraries were screened in a breast cancer cell line engineered to report Notch. Pathway analyses revealed MAPK-ERK signaling to be the predominant JAG1/Notch regulator and this was supported by gene set enrichment [...]

Cet article passe en revue les travaux récents sur le rôle joué par les protéines matricellulaires à l'intérieur du micro-environnement pour favoriser la progression tumorale

Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis

Wong, G. S. ; Rustgi, A. K.

Matricellular proteins have been classified as a family of non-structural matrix proteins capable of modulating a variety of biological processes within the extracellular matrix (ECM). These proteins are expressed dynamically and their cellular functions are highly dependent upon cues from the local environment. Recent studies have shown an increasing appreciation of the key roles these ECM proteins play within the tumour microenvironment. Induced by either tumour cells or tumour stromal [...]

Menée in vitro, in vivo et sur des échantillons prélevés sur des patients atteints d'une leucémie lymphocytaire chronique, d'une leucémie lymphoblastique aiguë ou d'un lymphome à cellules du manteau, cette étude met en évidence le rôle joué par l'expression du gène PKC-

Protein Kinase C-

Lutzny, Gloria ; Kocher, Thomas ; Schmidt-Supprian, Marc ; Rudelius, Martina ; Klein-Hitpass, Ludger ; Finch, Andrew J ; Dürig, Jan ; Wagner, Michaela ; Haferlach, Claudia ; Kohlmann, Alexander ; Schnittger, Susanne ; Seifert, Marc ; Wanninger, Stefan ; Zaborsky, Nadja ; Oostendorp, Robert ; Ruland, Jürgen ; Leitges, Michael ; Kuhnt, Toni ; Schäfer, Yvonne ; Lampl, Benedikt ; Peschel, Christian ; Egle, Alexander ; Ringshausen, Ingo

Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here, we describe a survival signaling pathway activated in stromal cells by contact to B cells from patients with chronic lymphocytic leukemia (CLL). The expression of protein kinase C (PKC)-

Cet article passe en revue les travaux récents sur les mécanismes moléculaires des processus invasif et métastatique d'un cancer du poumon

Key molecular mechanisms in lung cancer invasion and metastasis: A comprehensive review

Perlikos, Fotis ; Harrington, Kevin J. ; Syrigos, Konstantinos N.

Lung cancer remains one of the most common and malignant cancers worldwide. It is most often diagnosed at late stages, when it has already presented local invasion and distal metastases. The basic stages of invasion and metastasis involve the detachment of tumor cells from the extracellular matrix, invasion of surrounding tissues and basal lamina, intravasation into the blood stream, survival and transport through the blood stream, migration, arrest and extravasation at a distal site and [...]

Menée in vitro et à l'aide d'échantillons prélevés sur des patientes atteintes d'un cancer du sein métastatique, cette étude suggère que le micro-ARN 708 joue un rôle de suppresseur de métastases

Suppression of miRNA-708 by Polycomb Group Promotes Metastases by Calcium-Induced Cell Migration

Ryu, Seongho ; McDonnell, Kevin ; Choi, Hyejin ; Gao, Dingcheng ; Hahn, Mary ; Joshi, Natasha ; Park, Sun-Mi ; Catena, Raul ; Do, Yoonkyung ; Brazin, Jacqueline ; Vahdat, Linda T ; Silver, Randi B ; Mittal, Vivek

The progression of cancer to metastatic disease is a major cause of death. We identified miR-708 being transcriptionally repressed by polycomb repressor complex 2-induced H3K27 trimethylation in metastatic breast cancer. miR-708 targets the endoplasmic reticulum protein neuronatin to decrease intracellular calcium level, resulting in reduction of activation of ERK and FAK, decreased cell migration, and impaired metastases. Ectopic expression of neuronatin refractory to suppression by miR-708 [...]

Menée sur une matrice tridimensionnelle de collagène, cette étude met en évidence, par une technique d'imagerie confocale, la dynamique du processus invasif de cellules de cancer du sein métastatique

Minimization of thermodynamic costs in cancer cell invasion

Liu, Liyu ; Duclos, Guillaume ; Sun, Bo ; Lee, Jeongseog ; Wu, Amy ; Kam, Yoonseok ; Sontag, Eduardo D. ; Stone, Howard A. ; Sturm, James C. ; Gatenby, Robert A. ; Austin, Robert H.

Metastasis, the truly lethal aspect of cancer, occurs when metastatic cancer cells in a tumor break through the basement membrane and penetrate the extracellular matrix. We show that MDA-MB-231 metastatic breast cancer cells cooperatively invade a 3D collagen matrix while following a glucose gradient. The invasion front of the cells is a dynamic one, with different cells assuming the lead on a time scale of 70 h. The front cell leadership is dynamic presumably because of metabolic costs [...]

Cet article passe en revue les études précliniques récentes ayant utilisé des modèles murins avec mutations du gène p53

The mutant p53 mouse as a pre-clinical model

Jackson, J. G. ; Lozano, G.

The p53 tumor-suppressor pathway is dismantled in the development of most cancers. Mice with various p53 mutant alleles either singly or in combination with other genetic alterations are predisposed to tumor development. Here, we review studies utilizing p53 mutant mice that have recapitulated and informed clinical observations. These studies have demonstrated the p53 contribution, sometimes beneficial and sometimes detrimental, to treatment response in lymphomas, and lung and breast cancers. [...]

Cette étude présente un modèle murin caractérisé par une activation du gène p16/INK4a à l'intérieur des cellules tumorales et des cellules stromales environnantes

Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model

Burd, Christin E ; Sorrentino, Jessica A ; Clark, Kelly S ; Darr, David B ; Krishnamurthy, Janakiraman ; Deal, Allison M ; Bardeesy, Nabeel ; Castrillon, Diego H ; Beach, David H ; Sharpless, Norman E

Monitoring cancer and aging in vivo remains experimentally challenging. Here, we describe a luciferase knockin mouse (p16LUC), which faithfully reports expression of p16INK4a, a tumor suppressor and aging biomarker. Lifelong assessment of luminescence in p16+/LUC mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice. Expression of p16INK4a with aging did not predict cancer development, suggesting that the accumulation [...]