A l'aide de données issues du projet "The Cancer Genome Atlas" portant sur 863 échantillons tumoraux, cette étude identifie les régions non codantes qui, impliquées dans la régulation de l'expression des gènes, font l'objet de fréquentes mutations

Genome-wide analysis of noncoding regulatory mutations in cancer

Weinhold, Nils ; Jacobsen, Anders ; Schultz, Nikolaus ; Sander, Chris ; Lee, William

Cancer primarily develops because of somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing the discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here we analyze the complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify noncoding regions that are recurrently mutated in [...]

Menée sur une cohorte de 196 patients atteints d'une leucémie aiguë lymphoblastique de lignée T (64 adultes, 132 enfants), cette étude analyse l'expression différentielle de 148 gènes en présence de translocations du gène MYC

Genetic profile of T-cell acute lymphoblastic leukemias with MYC-translocations

La Starza, Roberta ; Borga, Chiara ; Barba, Gianluca ; Pierini, Valentina ; Schwab, Claire ; Matteucci, Caterina ; Lema Fernandez, Anair G. ; Leszl, Anna ; Cazzaniga, Gianni ; Chiaretti, Sabina ; Basso, Giuseppe ; Harrison, Christine J. ; te Kronnie, Geertruy ; Mecucci, Cristina

MYC-translocations represent a genetic subtype of T-lineage acute lymphoblastic leukemia (T-ALL), which occurs at an incidence of approximately 6%, assessed within a cohort of 196 T-ALL patients (64 adults and 132 children). The translocations were of two types; those rearranged with the T-cell receptor loci (TCR) and those with other partners. MYC-translocations were significantly associated with the TAL/LMO subtype of T-ALL (p=0,018) and trisomies 6 (p<0,001) and 7 (p<0,001). Within the [...]

Menée sur 206 patients pédiatriques atteints d'une leucémie aiguë lymphoblastique de la lignée B, cette étude identifie la présence fréquente de mutations somatiques de gènes activant la voie de signalisation Ras (KRAS, NRAS, FLT3 et PTPN11) puis, à l'aide de xénogreffes, suggère l'intérêt thérapeutique du selumetinib, un inhibiteur de MEK 1/2

Ras pathway mutations are highly prevalent in relapsed childhood acute lymphoblastic leukaemia, may act as relapse-drivers and confer sensitivity to MEK inhibition

Irving, Julie ; Matheson, Elizabeth ; Minto, Lynne ; Blair, Helen ; Case, Marian ; Halsey, Christina ; Swidenbank, Isabella ; Ponthan, Frida ; Kirschner-Schwabe, Renate ; Groeneveld-Krentz, Stefanie ; Hof, Jana ; Allan, James ; Harrison, Christine ; Vormoor, Josef ; von Stackelberg, Arend ; Eckert, Cornelia

For most children who relapse with acute lymphoblastic leukaemia, the prognosis is poor and there is a need for novel therapies to improve outcome. We screened samples from children with B lineage ALL entered into the ALL-REZ BFM 2002 clinical trial (ClinicalTrials.gov identifier: NCT00114348) for somatic mutations activating the Ras pathway (KRAS, NRAS, FLT3 and PTPN11) and showed mutation to be highly prevalent (76 from 206). Clinically, they were associated with high risk features including [...]

A partir d'échantillons tumoraux prélevés sur 44 patients atteints d'un carcinome à cellules acineuses du pancréas, cette étude identifie plusieurs anomalies génomiques susceptibles de faire l'objet de thérapies ciblées, notamment des inhibiteurs de MEK ou de PARP

Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes

Chmielecki, Juliann ; Hutchinson, Katherine E. ; Frampton, Garrett M. ; Chalmers, Zachary R ; Johnson, Adrienne ; Shi, Chanjuan ; Elvin, Julia ; Ali, Siraj M. ; Ross, Jeffrey S ; Basturk, Olca ; Balasubramanian, Sohail ; Lipson, Doron ; Yelensky, Roman ; Pao, William ; Miller, Vincent A ; Klimstra, David S ; Stephens, Philip J

Pancreatic acinar cell carcinomas (PACCs) account for ~1% (~500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiation have demonstrated limited efficacy against these tumors. Comprehensive genomic profiling of a large series of PACCs (n=44) identified recurrent rearrangements involving BRAF and RAF1 (CRAF) in ~23% of tumors. The most prevalent fusion, SND1-BRAF, results in activation [...]

Menée sur 60 échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate de stade avancé, cette étude met en évidence des mécanismes associés à une hypermutation du génome, notamment des gènes de réparation des mésappariements de l'ADN

Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer

Pritchard, Colin C. ; Morrissey, Colm ; Kumar, Akash ; Zhang, Xiaotun ; Smith, Christina ; Coleman, Ilsa ; Salipante, Stephen J. ; Milbank, Jennifer ; Yu, Ming ; Grady, William M. ; Tait, Jonathan F. ; Corey, Eva ; Vessella, Robert L. ; Walsh, Tom ; Shendure, Jay ; Nelson, Peter S.

A hypermutated subtype of advanced prostate cancer was recently described, but prevalence and mechanisms have not been well-characterized. Here we find that 12% (7 of 60) of advanced prostate cancers are hypermutated, and that all hypermutated cancers have mismatch repair gene mutations and microsatellite instability (MSI). Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing. Our findings identify parallels and differences in the [...]

Menée sur 12 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients afro-américains atteints d'un cancer colorectal, cette étude de séquençage de l'exome entier identifie notamment la présence fréquente d'une mutation somatique du gène APC

Identification of novel mutations by exome sequencing in African American colorectal cancer patients

Ashktorab, Hassan ; Daremipouran, Mohammad ; Devaney, Joe ; Varma, Sudhir ; Rahi, Hamed ; Lee, Edward ; Shokrani, Babak ; Schwartz, Russell ; Nickerson, Michael L. ; Brim, Hassan

BACKGROUND : The purpose of this study was to identify genome-wide single nucleotide variants and mutations in African American patients with colorectal cancer (CRC). There is a need of such studies in African Americans, because they display a higher incidence of aggressive CRC tumors. METHODS : We performed whole exome sequencing (WES) on DNA from 12 normal/tumor pairs of African American CRC patient tissues. Data analysis was performed using the software package GATK (Genome Analysis Tool [...]

Cet article passe en revue les travaux récents sur l'identification d'anomalies génétiques et épigénétiques dans les glioblastomes multtiformes

Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date

Bastien, Jayson I. L. ; McNeill, Katharine A. ; Fine, Howard A.

During the last decade, extensive multiplatform genome-wide analysis has yielded a wealth of knowledge regarding the genetic and molecular makeup of glioblastoma multiforme (GBM). These profiling studies support the emerging view that GBM comprises a group of highly heterogeneous tumor types, each with its own distinct molecular and genetic signatures. This heterogeneity complicates the process of defining reliable intertumor/intratumor biological states, which will ultimately be needed for [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la voie de signalisation dépendant de la protéine G[alpha]13 exerce une fonction de suppresseur de tumeurs dans une forme de lymphome diffus à grandes cellules B

Loss of signalling via G[alpha]13 in germinal centre B-cell-derived lymphoma

Muppidi, Jagan R. ; Schmitz, Roland ; Green, Jesse A. ; Xiao, Wenming ; Larsen, Adrien B. ; Braun, Sterling E. ; An, Jinping ; Xu, Ying ; Rosenwald, Andreas ; Ott, German ; Gascoyne, Randy D. ; Rimsza, Lisa M. ; Campo, Elias ; Jaffe, Elaine S. ; Delabie, Jan ; Smeland, Erlend B. ; Braziel, Rita M. ; Tubbs, Raymond R. ; Cook, J. R. ; Weisenburger, Dennis D. ; Chan, Wing C. ; Vaidehi, Nagarajan ; Staudt, Louis M. ; Cyster, Jason G.

Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a G

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, via la phosphorylation de ERK1/2, la protéine IER3 favorise l'oncogenèse associée à la mutation 12D du gène KRAS dans le pancréas

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

Garcia, Maria No ; xE, ; Grasso, Daniel ; Lopez-Millan, Maria Belen ; Hamidi, Tewfik ; Loncle, Celine ; Tomasini, Richard ; Lomberk, Gwen ; Porteu, Fran ; oise, ; Urrutia, Raul ; Iovanna, Juan L.

Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par le facteur de transcription ASCL1 dans le développement d'une tumeur neuroendocrine agressive du poumon

ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

Augustyn, Alexander ; Borromeo, Mark ; Wang, Tao ; Fujimoto, Junya ; Shao, Chunli ; Dospoy, Patrick D. ; Lee, Victoria ; Tan, Christopher ; Sullivan, James P. ; Larsen, Jill E. ; Girard, Luc ; Behrens, Carmen ; Wistuba, Ignacio I. ; Xie, Yang ; Cobb, Melanie H. ; Gazdar, Adi F. ; Johnson, Jane E. ; Minna, John D.

Aggressive neuroendocrine lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), represent an understudied tumor subset that accounts for approximately 40,000 new lung cancer cases per year in the United States. No targeted therapy exists for these tumors. We determined that achaete-scute homolog 1 (ASCL1), a transcription factor required for proper development of pulmonary neuroendocrine cells, is essential for the survival of a majority of lung cancers [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en induisant l'expression de CXCL13 dans les myofibroblastes tumoraux, une hypoxie favorise la progression d'un cancer de la prostate

Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts

Ammirante, Massimo ; Shalapour, Shabnam ; Kang, Youngjin ; Jamieson, Christina A. M. ; Karin, Michael

Prostate cancer (PC) is a slowly progressing malignancy that often responds to androgen ablation or chemotherapy by becoming more aggressive, acquiring a neuroendocrine phenotype, and undergoing metastatic spread. We found that B lymphocytes recruited into regressing androgen-deprived tumors by C-X-C motif chemokine 13 (CXCL13), a chemokine whose expression correlates with clinical severity, play an important role in malignant progression and metastatic dissemination of PC. We now describe how [...]

Menée à l'aide de modèles murins d'adénocarcinome du poumon, cette étude présente l'intérêt d'une technologie d'édition du génome, CRISPR-Cas9, pour analyser les conséquences fonctionnelles de mutations génétiques

CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling

Platt, Randall J ; Chen, Sidi ; Zhou, Yang ; Yim, Michael J ; Swiech, Lukasz ; Kempton, Hannah R ; Dahlman, James E ; Parnas, Oren ; Eisenhaure, Thomas M ; Jovanovic, Marko ; Graham, Daniel B ; Jhunjhunwala, Siddharth ; Heidenreich, Matthias ; Xavier, Ramnik J ; Langer, Robert ; Anderson, Daniel G ; Hacohen, Nir ; Regev, Aviv ; Feng, Guoping ; Sharp, Phillip A ; Zhang, Feng

CRISPR-Cas9 is a versatile genome editing technology for studying the functions of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse. We demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells. Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three [...]

Cet article présente une méthode qui, à l'aide de transposons, permet de créer des modèles murins pour mener des études de validation de plusieurs gènes mutés associés au cancer

Polygenic in vivo validation of cancer mutations using transposons

Chew, Su Kit ; Lu, Dong ; Campos, Lia ; Scott, Kenneth ; Saci, Abdel ; Collinson, Adam ; Raine, Keiran ; Hinton, Jonathan ; Teague, Jon ; Jones, David ; Menzies, Andrew ; Butler, Adam ; Gamble, John ; O'Meara, Sarah ; McLaren, Stuart ; Chin, Lynda ; Liu, Pentao ; Futreal, P. Andrew

The in vivo validation of cancer mutations and genes identified in cancer genomics is resource-intensive because of the low throughput of animal experiments. We describe a mouse model that allows multiple cancer mutations to be validated in each animal line. Animal lines are generated with multiple candidate cancer mutations using transposons. The candidate cancer genes are tagged and randomly expressed in somatic cells, allowing easy identification of the cancer genes involved in the generated [...]