A partir d'échantillons tumoraux prélevés sur 18 patients atteints d'un carcinome mucoépidermoïde des glandes salivaires, cette étude identifie un ensemble d'anomalies somatiques, notamment la présence fréquente de la translocation MECT1-MAML2 et de mutations des gènes TP53 et POU6F2

Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma

Kang, Hyunseok ; Tan, Marietta ; Bishop, Justin A. ; Jones, Sian ; Sausen, Mark ; Ha, Patrick K. ; Agrawal, Nishant

Purpose: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors. Experimental Design: Whole-exome sequencing and gene copy-number analyses were performed for 18 primary cancers with matched normal tissue. FISH was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors. Results: TP53 was the most commonly mutated gene in MEC (28%), and mutations [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en interaction avec les protéines NHA9 et MLL1, les protéines de fusion impliquant NUP98 favorisent le développement d'une léucémie

NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis

Xu, Haiming ; Valerio, Daria G ; Eisold, Meghan E ; Sinha, Amit ; Koche, Richard P ; Hu, Wenhuo ; Chen, Chun-wei ; Chu, S.  Haihua ; Brien, Gerard L ; Park, Christopher Y ; Hsieh, James J ; Ernst, Patricia ; Armstrong, Scott A

The nucleoporin 98 gene (NUP98) is fused to a variety of partner genes in multiple hematopoietic malignancies. Here, we demonstrate that NUP98 fusion proteins, including NUP98-HOXA9 (NHA9), NUP98-HOXD13 (NHD13), NUP98-NSD1, NUP98-PHF23, and NUP98-TOP1 physically interact with mixed lineage leukemia 1 (MLL1) and the non-specific lethal (NSL) histone-modifying complexes. Chromatin immunoprecipitation sequencing illustrates that NHA9 and MLL1 co-localize on chromatin and are found associated with [...]

Menée sur des lignées cellulaires de cancer du pancréas et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la signalisation mTORC2 favorise le développement et la progression d'une tumeur

mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer

Driscoll, David R. ; Karim, Saadia A. ; Sano, Makoto ; Gay, David M. ; Jacob, Wright ; Yu, Jun ; Mizukami, Yusuke ; Gopinathan, Aarthi ; Jodrell, Duncan I. ; Evans, T. R. Jeffry ; Bardeesy, Nabeel ; Hall, Michael N. ; Quattrochi, Brian J. ; Klimstra, David S. ; Barry, Simon T. ; Sansom, Owen J. ; Lewis, Brian C. ; Morton, Jennifer P.

mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor [...]

A partir d'échantillons tumoraux prélevés sur 16 patients chinois atteints d'un cancer colorectal, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en ciblant le gène KRAS, le micro-ARN miR-16 exerce une fonction de suppresseur de tumeurs

Deregulation of the miR-16-KRAS axis promotes colorectal cancer

You, Chaoying ; Liang, Hongwei ; Sun, Wu ; Li, Jialu ; Liu, Yanqing ; Fan, Qian ; Zhang, Haiyang ; Yue, Xin ; Li, Jing ; Chen, Xi ; Ba, Yi

KRAS plays a significant role in the etiology and progression of colorectal cancer (CRC), but the mechanism underlying this process has not been fully elucidated. In this study, we found that the KRAS protein levels were higher in CRC tissues than in the normal adjacent tissues, whereas its mRNA levels varied irregularly, suggesting that a post-transcriptional mechanism is involved in the regulation of KRAS. Then, we performed bioinformatic analyses to search for miRNAs that potentially target [...]

Cet article passe en revue les travaux récents sur la modélisation du rôle joué par différentes populations sous-clonales dans le processus métastatique

How subclonal modelling is changing the metastatic paradigm

Macintyre, Geoff ; Van Loo, Peter ; Corcoran, Niall M. ; Wedge, David C. ; Markowetz, Florian ; Hovens, Christopher M.

A concerted effort to sequence matched primary and metastatic tumours is vastly improving our ability to understand metastasis in humans. Compelling evidence has emerged that supports the existence of diverse and surprising metastatic patterns. Enhancing these efforts is a new class of algorithms that facilitate high-resolution subclonal modelling of metastatic spread. Here we summarise how subclonal models of metastasis are influencing the metastatic paradigm.

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, dans le stroma d'une tumeur du pancréas, des cellules cancéreuses induisent la formation d'un micro-environnement protégeant la tumeur des attaques du système immunitaire

Human pancreatic cancer cells induce a MyD88-dependent stromal response to promote a tumor-tolerant immune microenvironment

Delitto, Daniel ; Delitto, Andrea E. ; DiVita, Bayli B. ; Pham, Kien ; Han, Song ; Hartlage, Emily R. ; Newby, Brittney N. ; Gerber, Michael H. ; Behrns, Kevin E. ; Moldawer, Lyle L. ; Thomas, Ryan M. ; George, Thomas ; Brusko, Todd ; Mathews, Clayton E. ; Liu, Chen ; Trevino, Jose G. ; Hughes, Steven J. ; Wallet, Shannon

Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the crosstalk between pancreatic cancer (PC) and its TAS in primary human cell culture models. Upon exposure of TAS to PC cell-conditioned media, we documented robust secretion of IL-6 and IL-8. This TAS response was [...]

Cet article passe en revue les travaux récents ayant mis en évidence le rôle joué par le facteur de transcription GATA-2 dans la progression rapide d'un cancer de la prostate vers un stade métastatique

The role of GATA2 in lethal prostate cancer aggressiveness

Rodriguez-Bravo, Veronica ; Carceles-Cordon, Marc ; Hoshida, Yujin ; Cordon-Cardo, Carlos ; Galsky, Matthew D. ; Domingo-Domenech, Josep

Advanced prostate cancer is a classic example of the intractability and consequent lethality that characterizes metastatic carcinomas. Novel treatments have improved the survival of men with prostate cancer; however, advanced prostate cancer invariably becomes resistant to these therapies and ultimately progresses to a lethal metastatic stage. Consequently, detailed knowledge of the molecular mechanisms that control prostate cancer cell survival and progression towards this lethal stage of [...]

Cet article présente une méthode permettant de comparer les outils d'analyse bioinformatique visant à identifier, dans des données obtenues par séquençage de l'ADN, les gènes impliqués dans la cancérogenèse

Evaluating the evaluation of cancer driver genes

Tokheim, Collin J. ; Papadopoulos, Nickolas ; Kinzler, Kenneth W. ; Vogelstein, Bert ; Karchin, Rachel

Sequencing has identified millions of somatic mutations in human cancers, but distinguishing cancer driver genes remains a major challenge. Numerous methods have been developed to identify driver genes, but evaluation of the performance of these methods is hindered by the lack of a gold standard, that is, bona fide driver gene mutations. Here, we establish an evaluation framework that can be applied to driver gene prediction methods. We used this framework to compare the performance of eight [...]

A partir d'échantillons tumoraux prélevés sur 25 patients atteints d'un mélanome, cette étude évalue la faisabilité d'utiliser une technique de spectrométrie de masse pour identifier des néoépitopes d'intérêt clinique et définir une stratégie thérapeutique à base d'immunothérapies

Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry

Bassani-Sternberg, Michal ; Bräunlein, Eva ; Klar, Richard ; Engleitner, Thomas ; Sinitcyn, Pavel ; Audehm, Stefan ; Straub, Melanie ; Weber, Julia ; Slotta-Huspenina, Julia ; Specht, Katja ; Martignoni, Marc E. ; Werner, Angelika ; Hein, Rüdiger ; H. Busch, Dirk ; Peschel, Christian ; Rad, Roland ; Cox, Jürgen ; Mann, Matthias ; Krackhardt, Angela M.

Although mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. Using advanced mass spectrometry (MS) analysis, we survey the melanoma-associated immunopeptidome to a depth of 95,500 patient-presented peptides. We thereby discover a large spectrum of attractive target antigen candidates including cancer testis antigens and [...]