A partir d'échantillons tumoraux prélevés sur 98 patients atteints d'un adénocarcinome de l'ampoule de Vater, cette étude identifie de fréquentes mutations de gènes impliqués dans la signalisation WNT et des mutations du gène ELF3

Ampullary Cancers Harbor the Tumor Suppressor Gene ELF3 and Exhibit Frequent WNT Dysregulation

Gingras, Marie-Claude ; Covington, Kyle R ; Chang, David K ; Donehower, Lawrence A ; Gill, Anthony J ; Ittmann, Michael M ; Creighton, Chad J ; Johns, Amber L ; Shinbrot, Eve ; Dewal, Ninad ; Fisher, William E ; Pilarsky, Christian ; Grutzmann, Robert ; Overman, Michael J ; Jamieson, Nigel B ; Van Buren Ii, George ; Drummond, Jennifer ; Walker, Kimberly ; Hampton, Oliver A ; Xi, Liu ; Muzny, Donna M ; Doddapaneni, Harsha ; Lee, Sandra L ; Bellair, Michelle ; Hu, Jianhong ; Han, Yi ; Dinh, Huyen H ; Dahdouli, Mike ; Samra, Jaswinder S ; Bailey, Peter ; Waddell, Nicola ; Pearson, John V ; Harliwong, Ivon ; Wang, Huamin ; Aust, Daniela ; Oien, Karin A ; Hruban, Ralph H ; Hodges, Sally E ; McElhany, Amy ; Saengboonmee, Charupong ; Duthie, Fraser R ; Grimmond, Sean M ; Biankin, Andrew V ; Wheeler, David A ; Gibbs, Richard A

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. [...]

A partir de données portant sur 168 patients pédiatriques atteints d'un carcinome à cellules rénales, cette étude met en évidence la présence de réarrangements ALK chez 6 patients, puis suggère de recourir à ce biomarqueur pour définir un sous-type de la maladie et identifier des patients susceptibles de bénéficier de nouvelles options thérapeutiques

ALK-Rearranged Renal Cell Carcinomas in Children

Cajaiba, Mariana M. ; Jennings, Lawrence J. ; Rohan, Stephen M. ; Perez-Atayde, Antonio R. ; Marino-Enriquez, Adrian ; Fletcher, Jonathan A. ; Geller, James I. ; Leuer, Katrin M. C. ; Bridge, Julia A. ; Perlman, Elizabeth J.

Knowledge of the clinicopathological and molecular spectrum of pediatric renal cell carcinomas (RCCs) remains limited, and approximately 16-24% of these neoplasms cannot be classified into specific subtypes. In our review of 168 pediatric RCC prospectively registered on Children's Oncology Group AREN03B2 protocol, we identified six RCC (3.5%) that demonstrated a unique epithelioid morphology and a peculiar immunophenotypic profile that includes expression of ALK, TFE3 and retention of INI1. [...]

A partir d'échantillons tumoraux prélevés sur un total de 172 patients atteints d'un carcinome de l'ampoule de Vater, cette étude montre notamment que des mutations inactivant le gène ELF3 favorisent la croissance tumorale

Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma

Yachida, Shinichi ; Wood, Laura D ; Suzuki, Masami ; Takai, Erina ; Totoki, Yasushi ; Kato, Mamoru ; Luchini, Claudio ; Arai, Yasuhito ; Nakamura, Hiromi ; Hama, Natsuko ; Elzawahry, Asmaa ; Hosoda, Fumie ; Shirota, Tomoki ; Morimoto, Nobuhiko ; Hori, Kunio ; Funazaki, Jun ; Tanaka, Hikaru ; Morizane, Chigusa ; Okusaka, Takuji ; Nara, Satoshi ; Shimada, Kazuaki ; Hiraoka, Nobuyoshi ; Taniguchi, Hirokazu ; Higuchi, Ryota ; Oshima, Minoru ; Okano, Keiichi ; Hirono, Seiko ; Mizuma, Masamichi ; Arihiro, Koji ; Yamamoto, Masakazu ; Unno, Michiaki ; Yamaue, Hiroki ; Weiss, Matthew J ; Wolfgang, Christopher L ; Furukawa, Toru ; Nakagama, Hitoshi ; Vogelstein, Bert ; Kiyono, Tohru ; Hruban, Ralph H ; Shibata, Tatsuhiro

Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of [...]

Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un mélanome ou d'un cancer colorectal, cette étude met en évidence des mécanismes de nature épigénétique par lesquels, lorsqu'il comporte la mutation V600E, le gène BRAF réprime l'expression d'un ensemble de gènes

Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma

Fang, Minggang ; Hutchinson, Lloyd ; Deng, April ; Green, Michael R.

During cancer development, it is well established that many genes, including tumor suppressor genes, are hypermethylated and transcriptionally repressed, a phenomenon referred to as epigenetic silencing. In general, the factors involved in, and the mechanistic basis of, epigenetic silencing during cancer development are not well understood. We have recently described an epigenetic silencing pathway, directed by the oncogenic B-Raf proto-oncogene (BRAF) variant BRAF(V600E), that mediates [...]

Menée sur des modèles murins, cette étude met en évidence des mécanismes par lesquels un gène IDH1 muté favorise le développement d'une leucémie lymphoblastique aiguë T

Idh1 mutations contribute to the development of T-cell malignancies in genetically engineered mice

Hao, Zhenyue ; Cairns, Rob A. ; Inoue, Satoshi ; Li, Wanda Y. ; Sheng, Yi ; Lemonnier, François ; Wakeham, Andrew ; Snow, Bryan E. ; Dominguez-Brauer, Carmen ; Ye, Jing ; Larsen, Dana M. ; Straley, Kimberly S. ; Tobin, Erica R. ; Narayanaswamy, Rohini ; Gaulard, Philippe ; Mak, Tak W.

Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) are key drivers of hematopoietic malignancies. Although these mutations are most commonly associated with myeloid diseases, they also occur in malignancies of the T-cell lineage. To investigate their role in these diseases and provide tractable disease models for further investigation, we analyzed the T-cell compartment in a conditional knock-in (KI) mouse model of mutant Idh1. We observed the development of a spontaneous T-cell [...]

Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de l'œsophage, cette étude met en évidence des mécanismes par lesquels la protéine PSCA exerce une fonction de suppresseur de tumeurs

PSCA acts as a tumor suppressor by facilitating the nuclear translocation of RB1CC1 in esophageal squamous cell carcinoma

Zhang, Li-yi ; Wu, Jian-Lin ; Qiu, Hai-Bo ; Dong, Sui-Sui ; Zhu, Ying-Hui ; Lee, Victor Ho-Fun ; Qin, Yan-Ru ; Li, Yan ; Chen, Juan ; Liu, Hai-Bo ; Bi, Jiong ; Ma, Stephanie ; Guan, Xin-Yuan ; Fu, Li

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. By high-throughput transcriptome sequencing (RNA-Seq) profiling of 3 pairs of primary ESCCs and their corresponding nontumorous tissues, we identified prostate stem cell antigen (PSCA), a gene that encodes a glycosylphosphatidylinositol (GPI) anchored protein, is significantly down-regulated in ESCC. Here, we reported decreased expression of PSCA in 188/218 [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels des cellules tumorales circulantes parviennent à former des métastases à distance de l'organe où est localisée la tumeur primitive

Metastatic colonization by circulating tumour cells

Massagué, Joan ; Obenauf, Anna C.

Metastasis is the main cause of death in people with cancer. To colonize distant organs, circulating tumour cells must overcome many obstacles through mechanisms that we are only now starting to understand. These include infiltrating distant tissue, evading immune defences, adapting to supportive niches, surviving as latent tumour-initiating seeds and eventually breaking out to replace the host tissue. They make metastasis a highly inefficient process. However, once metastases have been [...]

Cet article passe en revue les travaux récents sur les processus de formation de métastases cérébrales d'un cancer du sein, puis analyse les leçons à tirer pour élaborer de nouvelles stratégies thérapeutiques

Breast cancer brain metastases: biology and new clinical perspectives

Witzel, Isabell ; Oliveira-Ferrer, Leticia ; Pantel, Klaus ; Müller, Volkmar ; Wikman, Harriet

Because of improvements in the treatment of patients with metastatic breast cancer, the development of brain metastases (BM) has become a major limitation of life expectancy and quality of life for many breast cancer patients. The improvement of management strategies for BM is thus an important clinical challenge, especially among high-risk patients such as human epidermal growth factor receptor 2-positive and triple-negative patients. However, the formation of BM as a multistep process is thus [...]

Menée in vitro et in vivo sur des modèles de cancer du sein, cette étude met en évidence des mécanismes par lesquels la protéine Wnt7a, secrétée par les cellules cancéreuses, favorise les processus invasif et métastatique

Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness

Avgustinova, Alexandra ; Iravani, Marjan ; Robertson, David ; Fearns, Antony ; Gao, Qiong ; Klingbeil, Pamela ; Hanby, Andrew M. ; Speirs, Valerie ; Sahai, Erik ; Calvo, Fernando ; Isacke, Clare M.

Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, [...]

A partir de données issues du projet "The Cancer Genome Atlas" et portant sur 904 tumeurs (14 types de cancer), cette étude montre que, pour plusieurs types de cancer (estomac, poumon, vessie, côlon...), les tumeurs connaissent un processus d'évolution neutre modélisé par une simple loi de puissance

Identification of neutral tumor evolution across cancer types

Williams, Marc J. ; Werner, Benjamin ; Barnes, Chris P. ; Graham, Trevor A. ; Sottoriva, Andrea

Despite extraordinary efforts to profile cancer genomes, interpreting the vast amount of genomic data in the light of cancer evolution remains challenging. Here we demonstrate that neutral tumor evolution results in a power-law distribution of the mutant allele frequencies reported by next-generation sequencing of tumor bulk samples. We find that the neutral power law fits with high precision 323 of 904 cancers from 14 types and from different cohorts. In malignancies identified as evolving [...]

Menée à l'aide d'une technique de séquençage du génome entier sur des échantillons sanguins prélevés sur 268 patients atteints d'une leucémie lymphocytaire chronique, cette étude met en évidence le rôle joué par la méthylation de l'ADN durant la phase de maturation des lymphocytes B

DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia

Oakes, Christopher C. ; Seifert, Marc ; Assenov, Yassen ; Gu, Lei ; Przekopowitz, Martina ; Ruppert, Amy S. ; Wang, Qi ; Imbusch, Charles D. ; Serva, Andrius ; Koser, Sandra D. ; Brocks, David ; Lipka, Daniel B. ; Bogatyrova, Olga ; Weichenhan, Dieter ; Brors, Benedikt ; Rassenti, Laura ; Kipps, Thomas J. ; Mertens, Daniel ; Zapatka, Marc ; Lichter, Peter ; Döhner, Hartmut ; Küppers, Ralf ; Zenz, Thorsten ; Stilgenbauer, Stephan ; Byrd, John C. ; Plass, Christoph

Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells [...]