A partir d'échantillons tumoraux prélevés sur 18 004 patients adultes atteints d'une tumeur solide, cette étude identifie notamment un ensemble d'anomalies génomiques rares associées à diverses localisations cancéreuses

High-throughput genomic profiling of adult solid tumors reveals novel insights into cancer pathogenesis

Hartmaier, Ryan J. ; Albacker, Lee ; Chmielecki, Juliann ; Bailey, Mark ; He, Jie ; Goldberg, Michael ; Ramkissoon, Shakti ; Suh, James ; Elvin, Julia A. ; Chiacchia, Samuel ; Frampton, Garrett M. ; Ross, Jeffrey S. ; Miller, Vincent ; Stephens, Philip J. ; Lipson, Doron

Genomic profiling is widely predicted to become a standard of care in clinical oncology, but more effective data sharing to accelerate progress in precision medicine will be required. Here we describe cancer-associated genomic profiles from 18,004 unique adult cancers. The dataset was composed of 162 tumor subtypes including multiple rare and uncommon tumors. Comparison of alteration frequencies to The Cancer Genome Atlas (TCGA) identified some differences and suggested an enrichment of [...]

Menée sur des lignées cellulaires de lymphome folliculaire et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en supprimant l'expression du gène NOTCH2, BCL6 favorise la survie des cellules cancéreuses

BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells

Valls, Ester ; Lobry, Camille ; Geng, Huimin ; Wang, Ling ; Cardenas, Mariano ; Rivas, Martin ; Cerchietti, Leandro ; Oh, Philmo ; Yang, Shao Ning ; Oswald, Erin ; Graham, Camille W. ; Jiang, Yanwen ; Hatzi, Katerina ; Agirre, Xabier ; Perkey, Eric ; Li, Zhuoning ; Tam, Wayne ; Bhatt, Kamala ; Leonard, John P. ; Zweidler-McKay, Patrick A. ; Maillard, Ivan ; Elemento, Olivier ; Ci, Weimin ; Aifantis, Iannis ; Melnick, Ari

Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and Notch pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably BCL6 up-regulation is associated with repression of Notch2 and its target [...]

Menée in vitro et in vivo, cette étude met notamment en évidence des mécanismes par lesquels le récepteur de la vitamine D régule l'autophagie dans des cellules de tumeurs mammaires

Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells

Tavera-Mendoza, Luz E. ; Westerling, Thomas ; Libby, Eric ; Marusyk, Andriy ; Cato, Laura ; Cassani, Raymundo ; Cameron, Lisa A. ; Ficarro, Scott B. ; Marto, Jarrod A. ; Klawitter, Jelena ; Brown, Myles

Women in North America have a one in eight lifetime risk of developing breast cancer (BC), and a significant proportion of these individuals will develop recurrent BC and will eventually succumb to the disease. Metastatic, therapy-resistant BC cells are refractory to cell death induced by multiple stresses. Here, we document that the vitamin D receptor (VDR) acts as a master transcriptional regulator of autophagy. Activation of the VDR by vitamin D induces autophagy and an autophagic [...]

Menée à l'aide de modèles murins de divers types de cancer (sein, lymphome, sarcome), cette étude met en évidence des mécanismes par lesquels, en présence d'interféron gamma dans le micro-environnement tumoral, des lymphocytes T cytotoxiques favorisent l'échappement de la tumeur au système immunitaire

IFN-gamma is required for cytotoxic T cell-dependent cancer genome immunoediting

Takeda, Kazuyoshi ; Nakayama, Masafumi ; Hayakawa, Yoshihiro ; Kojima, Yuko ; Ikeda, Hiroaki ; Imai, Naoko ; Ogasawara, Kouetsu ; Okumura, Ko ; Thomas, David M. ; Smyth, Mark J.

Genetic evolution that occurs during cancer progression enables tumour heterogeneity, thereby fostering tumour adaptation, therapeutic resistance and metastatic potential. Immune responses are known to select (immunoedit) tumour cells displaying immunoevasive properties. Here we address the role of IFN-

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la protéine WASF3 favorise le processus invasif de cellules cancéreuses présentant un gène KRAS muté

Promotion of Invasion by Mutant RAS is Dependent on Activation of the WASF3 Metastasis Promoter Gene

Teng, Yong ; Ngoka, Lambert ; Cowell, John K.

Metastasis represents an end stage in the evolution of cancer progression and has been related to specific genetic pathways. Overexpression of mutant RAS in particular appears to promote invasion and metastasis, although exactly how this occurs has not been well characterized. We have previously shown that activation of the WASF3 protein regulates actin cytoskeleton dynamics that promote invasion. In this report we investigated how WASF3 overexpression interacts with mutant RAS to increased [...]

Menée à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un cancer (poumon, ovaire, côlon-rectum, sein, mélanome), puis à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en induisant un endothélium pro inflammatoire et sénescent, la signalisation Notch favorise le processus métastatique

Endothelial Notch1 Activity Facilitates Metastasis

Wieland, Elfriede ; Rodriguez-Vita, Juan ; Liebler, Sven S. ; Mogler, Carolin ; Moll, Iris ; Herberich, Stefanie E. ; Espinet, Elisa ; Herpel, Esther ; Menuchin, Amitai ; Chang-Claude, Jenny ; Hoffmeister, Michael ; Gebhardt, Christoffer ; Brenner, Hermann ; Trumpp, Andreas ; Siebel, Christian W. ; Hecker, Markus ; Utikal, Jochen ; Sprinzak, David ; Fischer, Andreas

Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en régulant des processus inflammatoires dans le micro-environnement tumoral, la lipocaline 2 favorise la croissance d'un adénocarcinome canalaire du pancréas

Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment

Gomez-Chou, Sobeyda ; Swidnicka-Siergiejko, Agnieszka ; Badi, Niharika ; Chavez-Tomar, Myrriah ; Lesinski, Gregory B. ; Bekaii-Saab, Tanios ; Farren, Matthew R. ; Mace, Thomas A. ; schmidt, carl ; Liu, Yan ; Deng, Defeng ; Hwang, Rosa F. ; Zhou, Liran ; Moore, Todd T. ; Chatterjee, Deyali ; Wang, Huamin ; Leng, Xiaohong ; Arlinghaus, Ralph B. ; Logsdon, Craig D. ; Cruz-Monserrate, Zobeida

Lipocalin-2 (LCN2) promotes malignant development in many cancer types. LCN2 is upregulated in patients with pancreatic ductal adenocarcinoma (PDAC) and in obese individuals, but whether it contributes to PDAC development is unclear. In this study, we investigated the effects of Lcn2 depletion on diet-induced obesity, inflammation and PDAC development. Mice with acinar cell-specific expression of KrasG12D were crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of [...]

A partir d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un cancer du côlon, puis menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels un ARN circulaire, CCDC66, favorise la progression tumorale et le processus métastatique

Non-coding effects of circular RNA CCDC66 promote colon cancer growth and metastasis

Hsiao, Kuei-Yang ; Lin, Ya-Chi ; Gupta, Sachin Kumar ; Chang, Ning ; Yen, Laising ; Sun, H. Sunny ; Tsai, Shaw-Jenq

Circular RNA (circRNA) is a class of non-coding RNA whose functions remain mostly unknown. Recent studies indicate circRNA may be involved in disease pathogenesis, but direct evidence is scarce. Here we characterize the functional role of a novel circRNA, circCCDC66, in colorectal cancer (CRC). RNA-Seq data from matched normal and tumor colon tissue samples identified numerous circRNAs specifically elevated in cancer cells, several of which were verified by quantitative RT-PCR. CircCCDC66 [...]

A partir d'échantillons tumoraux prélevés sur plus de 4 000 patients atteints d'un cancer du cerveau, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en réprimant l'expression du gène LIF, la protéine ZEB1 régule la survie des cellules souches de gliome

ZEB1 regulates glioma stemness through LIF repression

Edwards, Lincoln A. ; Li, Aiguo ; Berel, Dror ; Madany, Mecca ; Kim, Nam-Ho ; Liu, Minzhi ; Hymowitz, Mitch ; Uy, Benjamin ; Jung, Rachel ; Xu, Minlin ; Black, Keith L. ; Rentsendorj, Altan ; Fan, Xuemo ; Zhang, Wei ; Yu, John S.

The identification of a stem cell regulatory gene which is aberrantly expressed in glioma and associated with patient survival would increase the understanding of the role of glioma cancer stem cells (GCSCs) in the virulence of gliomas. Interrogating the genomes of over 4000 brain cancers we identified ZEB1 deletion in ~15% (grade II and III) and 50% of glioblastomas. Meta-analysis of ZEB1 copy number status in 2,988 cases of glioma revealed disruptive ZEB1 deletions associated with decreased [...]

A partir de l'analyse d'une base de données comprenant 70 000 variants du gène TP53, cet article présente des recommandations pour la validation, le contrôle de qualité et la notification du statut du gène TP53 en pratique clinique

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

Leroy, Bernard ; Ballinger, Mandy L. ; Baran-Marszak, Fanny ; Bond, Gareth L. ; Braithwaite, Antony ; Concin, Nicole ; Donehower, Lawrence A. ; El-Deiry, Wafik S. ; Fenaux, Pierre ; Gaidano, Gianluca ; Langerød, Anita ; Hellstrom-Lindberg, Eva ; Iggo, Richard ; Lehmann-Che, Jacqueline ; Mai, Phuong L. ; Malkin, David ; Moll, Ute M. ; Myers, Jeffrey N. ; Nichols, Kim E. ; Pospisilova, Sarka ; Ashton-Prolla, Patricia ; Rossi, Davide ; Savage, Sharon A. ; Strong, Louise C. ; Tonin, Patricia N. ; Zeillinger, Robert ; Zenz, Thorsten ; Fraumeni, Joseph F. ; Taschner, Peter E. M. ; Hainaut, Pierre ; Soussi, Thierry

Accurate assessment of TP53 gene status in sporadic tumors and in the germline of individuals at high risk of cancer due to Li–Fraumeni Syndrome (LFS) has important clinical implications for diagnosis, surveillance, and therapy. Genomic data from more than 20,000 cancer genomes provide a wealth of information on cancer gene alterations and have confirmed TP53 as the most commonly mutated gene in human cancer. Analysis of a database of 70,000 TP53 variants reveals that the two newly discovered [...]