A partir de données portant sur 10 250 génomes tumoraux (36 types de cancer), cette étude met en évidence des signatures révélatrices de processus ayant engendré des mutations à un rythme constant depuis la naissance

Clock-like mutational processes in human somatic cells

Alexandrov, Ludmil B. ; Jones, Philip H. ; Wedge, David C. ; Sale, Julian E. ; Campbell, Peter J. ; Nik-Zainal, Serena ; Stratton, Michael R.

During the course of a lifetime, somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals, and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer [...]

A partir d'échantillons (tumeurs primitives et lésions précancéreuses adjacentes) prélevés sur des patients atteints d'un mélanome, cette étude identifie la succession d'anomalies génétiques au cours de la progression d'un mélanome

The Genetic Evolution of Melanoma from Precursor Lesions

Shain, A. Hunter ; Yeh, Iwei ; Kovalyshyn, Ivanka ; Sriharan, Aravindhan ; Talevich, Eric ; Gagnon, Alexander ; Dummer, Reinhard ; North, Jeffrey ; Pincus, Laura ; Ruben, Beth ; Rickaby, William ; D’Arrigo, Corrado ; Robson, Alistair ; Bastian, Boris C.

BACKGROUND : The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known. METHODS : We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas. RESULTS : Precursor lesions were initiated by mutations of genes that are known to activate [...]

Menée sur des lignées cellulaires de mélanome et de cancer papillaire de la thyroïde présentant un gène BRAF muté, cette étude met en évidence des mécanismes par lesquels, sous l'effet du gène BRAF muté, la surexpression du microARN miR-3151 induit l'inactivation du gène suppresseur de tumeurs p53

MicroRNA-3151 inactivates TP53 in BRAF-mutated human malignancies

Lankenau, Malori A. ; Patel, Ravi ; Liyanarachchi, Sandya ; Maharry, Sophia E. ; Hoag, Kevin W. ; Duggan, Megan ; Walker, Christopher J. ; Markowitz, Joseph ; Carson, William E. ; Eisfeld, Ann-Kathrin ; de la Chapelle, Albert

The B-Raf proto-oncogene serine/threonine kinase (BRAF) gene is the most frequently mutated gene in malignant melanoma (MM) and papillary thyroid cancer (PTC) and is causally involved in malignant cell transformation. Mutated BRAF is associated with an aggressive disease phenotype, thus making it a top candidate for targeted treatment strategies in MM and PTC. We show that BRAF mutations in both MM and PTC drive increased expression of oncomiR-3151, which is coactivated by the SP1/NF-κB [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une perturbation de la signalisation PTEN dans les lymphocytes T régulateurs du micro-environnement favorise la croissance tumorale

The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment

Sharma, Madhav D. ; Shinde, Rahul ; McGaha, Tracy L. ; Huang, Lei ; Holmgaard, Rikke B. ; Wolchok, Jedd D. ; Mautino, Mario R. ; Celis, Esteban ; Sharpe, Arlene H. ; Francisco, Loise M. ; Powell, Jonathan D. ; Yagita, Hideo ; Mellor, Andrew L. ; Blazar, Bruce R. ; Munn, David H.

The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels une sous-expression de l'enzyme ASS1 favorise la prolifération cancéreuse

Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis

Rabinovich, Shiran ; Adler, Lital ; Yizhak, Keren ; Sarver, Alona ; Silberman, Alon ; Agron, Shani ; Stettner, Noa ; Sun, Qin ; Brandis, Alexander ; Helbling, Daniel ; Korman, Stanley ; Itzkovitz, Shalev ; Dimmock, David ; Ulitsky, Igor ; Nagamani, Sandesh C. S. ; Ruppin, Eytan ; Erez, Ayelet

Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la perte d'expression du gène EphA2 favorise la prolifération cellulaire d'une tumeur du poumon présentant un gène Kras muté

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Yeddula, Narayana ; Xia, Yifeng ; Ke, Eugene ; Beumer, Joep ; Verma, Inder M.

Lung adenocarcinoma, a major form of non-small cell lung cancer, is the leading cause of cancer deaths. The Cancer Genome Atlas analysis of lung adenocarcinoma has identified a large number of previously unknown copy number alterations and mutations, requiring experimental validation before use in therapeutics. Here, we describe an shRNA-mediated high-throughput approach to test a set of genes for their ability to function as tumor suppressors in the background of mutant KRas and WT Tp53. We [...]

Cet article passe en revue les travaux récents sur les différentes fonctions du gène p53 dans les tumeurs du sein et leur micro-environnement

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

Wang, Xuyi ; Simpson, Evan R. ; Brown, Kristy A.

The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, [...]

Menée à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels une amplification du gène de l'enzyme ST3GAL1 favorise la croissance tumorale et le processus invasif d'un glioblastome

ST3GAL1-Associated Transcriptomic Program in Glioblastoma Tumor Growth, Invasion, and Prognosis

Chong, Yuk Kien ; Sandanaraj, Edwin ; Koh, Lynnette W. H. ; Thangaveloo, Moogaambikai ; Tan, Melanie S. Y. ; Koh, Geraldene R. H. ; Toh, Tan Boon ; Lim, Grace G. Y. ; Holbrook, Joanna D. ; Kon, Oi Lian ; Nadarajah, Mahendran ; Ng, Ivan ; Ng, Wai Hoe ; Tan, Nguan Soon ; Lim, Kah Leong ; Tang, Carol ; Ang, Beng Ti

Background: Cell surface sialylation is associated with tumor cell invasiveness in many cancers. Glioblastoma is the most malignant primary brain tumor and is highly infiltrative. ST3GAL1 sialyltransferase gene is amplified in a subclass of glioblastomas, and its role in tumor cell self-renewal remains unexplored. Methods: Self-renewal of patient glioma cells was evaluated using clonogenic, viability, and invasiveness assays. ST3GAL1 was identified from differentially expressed genes in Peanut [...]