A partir de données du projet "The Cancer Genome Atlas" portant sur les génomes de 64 tumeurs de types différents, cette étude met en évidence la prévalence du phénomène de chromothripsis (réarrangements génomiques massifs) selon les types de tumeurs et suggère un mécanisme susceptible de rendre compte de ce phénomène

Breakpoint profiling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology-independent mechanisms

Malhotra, Ankit ; Lindberg, Michael R ; Faust, Greg G ; Leibowitz, Mitchell L ; Clark, Royden A ; Layer, Ryan ; Quinlan, Aaron R ; Hall, Ira M

Tumor genomes are generally thought to evolve through a gradual accumulation of mutations, but the observation that extraordinarily complex rearrangements can arise through single mutational events suggests that evolution may be accelerated by punctuated changes in genome architecture. To assess the prevalence and origins of complex genomic rearrangements (CGRs), we mapped 6,179 somatic structural variation breakpoints in 64 cancer genomes from 7 tumor types and screened for clusters of three [...]

Menée sur des échantillons prélevés sur 149 patients atteints d'une leucémie lymphocytaire chronique, dont 18 patients ont subi deux prélèvements espacés dans le temps, cette étude met en évidence une hétérogénéité intratumorale et l'association d'une évolution clonale avec la chimiothérapie

Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Landau, Dan A ; Carter, Scott L ; Stojanov, Petar ; McKenna, Aaron ; Stevenson, Kristen ; Lawrence, Michael S ; Sougnez, Carrie ; Stewart, Chip ; Sivachenko, Andrey ; Wang, Lili ; Wan, Youzhong ; Zhang, Wandi ; Shukla, Sachet A ; Vartanov, Alexander ; Fernandes, Stacey M ; Saksena, Gordon ; Cibulskis, Kristian ; Tesar, Bethany ; Gabriel, Stacey ; Hacohen, Nir ; Meyerson, Matthew ; Lander, Eric S ; Neuberg, Donna ; Brown, Jennifer R ; Getz, Gad ; Wu, Catherine J

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells [...]

Menée sur des échantillons tumoraux prélevés sur 15 patientes atteintes d'un carcinome épidermoïde de la vulve, cette étude met notamment en évidence des délétions dans la région chromosomique 3p14 et la dérégulation fréquente du gène FHIT qui se trouve dans cette région

Genomic aberration patterns and expression profiles of squamous cell carcinomas of the vulva

Micci, Francesca ; Panagopoulos, Ioannis ; Haugom, Lisbeth ; Dahlback, Hanne-Sofie S. ; Pretorius, Maria E. ; Davidson, Ben ; Abeler, Vera M. ; Tropé, Claes G. ; Danielsen, Håvard E. ; Heim, Sverre

Little is known about the genomic abnormalities of squamous cell carcinomas (SCC) of the vulva and how they correlate with gene expression. We determined the genomic and expression profiles of 15 such SCC using karyotyping, DNA ploidy analysis, arrayCGH, and expression arrays. Four of the five cases with clonal chromosomal aberrations found by G-banding showed highly abnormal karyotypes with multiple rearrangements. The imbalances scored by arrayCGH mapped to different chromosomes with losses [...]

Menée sur des échantillons tumoraux prélevés sur 11 patients atteints d'un glioblastome, cette étude identifie une importante hétérogénéité entre différentes zones d'une tumeur et, à partir d'une reconstruction phylogénétique, met en évidence la dynamique évolutionniste à l'oeuvre dans la progression tumorale

Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics

Sottoriva, Andrea ; Spiteri, Inmaculada ; Piccirillo, Sara G. M. ; Touloumis, Anestis ; Collins, V. Peter ; Marioni, John C. ; Curtis, Christina ; Watts, Colin ; Tavare, Simon

Glioblastoma (GB) is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure. However, the extent of intratumor heterogeneity as a result of tumor evolution is still poorly understood. To address this, we developed a unique surgical multisampling scheme to collect spatially distinct tumor fragments from 11 GB [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels le gène Xist joue un rôle de suppresseur de tumeurs dans les cancers hématologiques

Xist RNA Is a Potent Suppressor of Hematologic Cancer in Mice

Yildirim, Eda ; Kirby, James E ; Brown, Diane E ; Mercier, Francois E ; Sadreyev, Ruslan I ; Scadden, David T ; Lee, Jeannie T

X chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'ubiquitine ligase RNF20 dans le développement d'une leucémie avec réarrangements MLL

Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia

Wang, Eric ; Kawaoka, Shinpei ; Yu, Ming ; Shi, Junwei ; Ni, Ting ; Yang, Wenjing ; Zhu, Jun ; Roeder, Robert G. ; Vakoc, Christopher R.

Mixed-lineage leukemia (MLL) fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here, we identify the histone H2B E3 ubiquitin ligase ring finger protein 20 (RNF20) as an [...]

Menée à l'aide de modèle murins et de xénogreffes, cette étude met en évidence des mécanismes par lesquels le gène Gfi1 favorise le développement d'une leucémie lymphoblastique aiguë

Growth Factor Independence 1 Antagonizes a p53-Induced DNA Damage Response Pathway in Lymphoblastic Leukemia

Khandanpour, Cyrus ; Phelan, James D ; Vassen, Lothar ; Schütte, Judith ; Chen, Riyan ; Horman, Shane R ; Gaudreau, Marie-Claude ; Krongold, Joseph ; Zhu, Jinfang ; Paul, William E ; Dührsen, Ulrich ; Göttgens, Bertie ; Grimes, H.  Leighton ; Möröy, Tarik

Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Because oncogenic signaling activates a p53-dependent DNA damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function because Gfi1 ablation exacerbates p53 responses and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and [...]

Cet article passe en revue les travaux récents sur le rôle joué par les neutrophiles, via la production de cytokines, dans le développement et la progression d'une tumeur

On the Cytokines Produced by Human Neutrophils in Tumors

Tecchio, Cristina ; Scapini, Patrizia ; Pizzolo, Giovanni ; Cassatella, Marco A.

Although traditionally viewed as short-lived innate immunity cells, only playing a crucial role in host defense toward infections, neutrophils have recently become subject of a new wave of research in diverse research areas including in tumors. Indeed, increasing experimental evidence indicate that neutrophils may directly or indirectly influence the tumor fate through the release of a wide array of molecules able to exert either pro-tumor or anti-tumor functions depending on the [...]

Menée in vitro et in vivo, cette étude met en évidence le role joué par la surexpression de PGC1

PGC1

Vazquez, Francisca ; Lim, Ji-Hong ; Chim, Helen ; Bhalla, Kavita ; Girnun, Geoff ; Pierce, Kerry ; Clish, Clary B ; Granter, Scott R ; Widlund, Hans R ; Spiegelman, Bruce M ; Puigserver, Pere

Cancer cells reprogram their metabolism using different strategies to meet energy and anabolic demands to maintain growth and survival. Understanding the molecular and genetic determinants of these metabolic programs is critical to successfully exploit them for therapy. Here, we report that the oncogenic melanocyte lineage-specification transcription factor MITF drives PGC1

A partir de données portant sur 1 019 échantillons prélevés sur des patientes atteintes d'un cancer séreux de l'ovaire, puis menée in vitro, cette étude met en évidence le rôle joué par un réseau de micro-ARNs, notamment miR-506, dans la répression d'une transition épithélio-mésenchymateuse

Integrated Analyses Identify a Master MicroRNA Regulatory Network for the Mesenchymal Subtype in Serous Ovarian Cancer

Yang, Da ; Sun, Yan ; Hu, Limei ; Zheng, Hong ; Ji, Ping ; Pecot, Chad V ; Zhao, Yanrui ; Reynolds, Sheila ; Cheng, Hanyin ; Rupaimoole, Rajesha ; Cogdell, David ; Nykter, Matti ; Broaddus, Russell ; Rodriguez-Aguayo, Cristian ; Lopez-Berestein, Gabriel ; Liu, Jinsong ; Shmulevich, Ilya ; Sood, Anil K ; Chen, Kexin ; Zhang, Wei

Integrated genomic analyses revealed a miRNA-regulatory network that further defined a robust integrated mesenchymal subtype associated with poor overall survival in 459 cases of serous ovarian cancer (OvCa) from The Cancer Genome Atlas and 560 cases from independent cohorts. Eight key miRNAs, including miR-506, miR-141, and miR-200a, were predicted to regulate 89% of the targets in this network. Follow-up functional experiments illustrate that miR-506 augmented E-cadherin expression, inhibited [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence l'existence d'une population de cellules souches dans les métastases cérébrales d'un cancer primitif du poumon

A Cancer Stem Cell Model for Studying Brain Metastases From Primary Lung Cancer

Nolte, Sara M. ; Venugopal, Chitra ; McFarlane, Nicole ; Morozova, Olena ; Hallett, Robin M. ; O’Farrell, Erin ; Manoranjan, Branavan ; Murty, Naresh K. ; Klurfan, Paula ; Kachur, Edward ; Provias, John P. ; Farrokhyar, Forough ; Hassell, John A. ; Marra, Marco ; Singh, Sheila K.

Background Brain metastases are most common in adults with lung cancer, predicting uniformly poor patient outcome, with a median survival of only months. Despite their frequency and severity, very little is known about tumorigenesis in brain metastases. Methods We applied previously developed primary solid tumor-initiating cell models to the study of brain metastases from the lung to evaluate the presence of a cancer stem cell population. Patient-derived brain metastases (n = 20) and the [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par une surexpression de la mucine MUC4 dans les processus invasif et métastatique d'un cancer du sein triplement négatif

MUC4 Overexpression Augments Cell Migration and Metastasis through EGFR Family Proteins in Triple Negative Breast Cancer Cells

Mukhopadhyay, Partha ; Lakshmanan, Imayavaramban ; Ponnusamy, Moorthy P. ; Chakraborty, Subhankar ; Jain, Maneesh ; Pai, Priya ; Smith, Lynette M. ; Lele, Subodh M. ; Batra, Surinder K.

Introduction : Current studies indicate that triple negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and an early pattern of metastasis. Emerging evidence suggests that MUC4 mucin is associated with metastasis of various cancers, including breast cancer. However, the functional role of MUC4 remains unclear in breast cancers, especially in TNBCs. Method : In the present study, we investigated the functional and mechanistic roles of MUC4 in [...]