A partir d'échantillons tumoraux prélevés sur 60 patients atteints d'un adénocarcinome péri-ampullaire, cette étude norvégienne identifie un ensemble d'anomalies génomiques et transcriptomiques

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma

Sandhu, Vandana ; Wedge, David C. ; Bowitz Lothe, Inger Marie ; Labori, Knut Jørgen ; Dentro, Stefan C. ; Buanes, Trond ; Skrede, Martina L. ; Dalsgaard, Astrid M. ; Munthe, Else ; Myklebost, Ola ; Lingjærde, Ole Christian ; Børresen-Dale, Anne-Lise ; Ikdahl, Tone ; Van Loo, Peter ; Nord, Silje ; Kure, Elin H.

Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number [...]

A partir d'échantillons sanguins prélevés à plusieurs moments du cours de la maladie sur 74 patients atteints d'une leucémie myéloïde aiguë, puis à l'aide de xénogreffes, cette étude française identifie l'évolution des mutations et translocations de la population clonale maligne

Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia

Hirsch, Pierre ; Zhang, Yanyan ; Tang, Ruoping ; Joulin, Virginie ; Boutroux, Helene ; Pronier, Elodie ; Moatti, Hannah ; Flandrin, Pascale ; Marzac, Christophe ; Bories, Dominique ; Fava, Fanny ; Mokrani, Hayat ; Betems, Aline ; Lorre, Florence ; Favier, Remi ; Feger, Frederic ; Mohty, Mohamad ; Douay, Luc ; Legrand, Ollivier ; Bilhou-Nabera, Chrystèle ; Louache, Fawzia ; Delhommeau, François

In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) [...]

A partir d'échantillons tumoraux prélevés sur 42 patients atteints d'un mésothéliome malin, cette étude identifie un ensemble d'anomalies génomiques, les gènes les plus fréquemment altérés étant BAP1, NF2 et CDKN2A/B

Genomic Landscape of Malignant Mesotheliomas

Kato, Shumei ; Tomson, Brett N. ; Buys, Timon P. H. ; Elkin, Sheryl K. ; Carter, Jennifer L. ; Kurzrock, Razelle

Understanding the genomic landscape of malignant mesothelioma may identify novel molecular drivers of this ultra-rare disease, which can lead to an expanded roster of targeted therapies and clinical trial options for patients with mesothelioma. We examined the molecular profiles of 42 patients with malignant mesothelioma (including pleural, peritoneal, and pericardial) that were referred by clinicians to be tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory using [...]

Cet article passe en revue les travaux récents sur l'identification d'anomalies génomiques impliquées dans le développement et la progression d'un myélome multiple, puis analyse les perspectives cliniques offertes par ces découvertes

Genomic complexity of multiple myeloma and its clinical implications

Manier, Salomon ; Salem, Karma Z. ; Park, Jihye ; Landau, Dan A. ; Getz, Gad ; Ghobrial, Irene M.

Multiple myeloma (MM) is a genetically complex disease that evolves from pre-malignant stages, such as monoclonal gammaopathy of undetermined significance and smouldering multiple myeloma, and progresses to symptomatic MM; this continuum provides a unique framework to study the sequential genomic evolution of MM. In the past 5 years, results from large-scale whole-exome sequencing studies have provided new insights into the clonal heterogeneity and evolution of the disease. Moreover, the [...]

A partir de 102 échantillons tumoraux prélevés sur 30 patients atteints d'un neuroblastome avec amplification du gène MYCN, cette étude met en évidence une hétérogénéité du nombre de copies de ce gène entre la tumeur primitive au diagnostic, la tumeur après le traitement et les métastases

Heterogeneity of MYCN amplification in neuroblastoma at diagnosis, treatment, relapse, and metastasis

Marrano, Paula ; Irwin, Meredith S. ; Thorner, Paul S.

Amplification of the MYCN gene in neuroblastoma is associated with a poor prognosis and is considered to remain unchanged in post-treatment specimens and metastases. While heterogeneity of MYCN copy number in tumor cells has been reported, serial samples have only been studied in a limited way, and the biologic relevance of this finding is not well understood. We used in situ hybridization on paraffin sections of 102 specimens from 30 patients with MYCN-amplified neuroblastoma to determine MYCN [...]

A partir de 775 échantillons tumoraux prélevés sur des patients atteints d'un méningiome, cettte étude identifie la présence de mutations dans divers gènes, notamment le gène POLR2A, susceptibles de définir des sous-groupes de patients présentant des caractéristiques cliniques distinctes

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

Clark, Victoria E. ; Harmanci, Akdes Serin ; Bai, Hanwen ; Youngblood, Mark W. ; Lee, Tong Ihn ; Baranoski, Jacob F. ; Ercan-Sencicek, A. Gulhan ; Abraham, Brian J. ; Weintraub, Abraham S. ; Hnisz, Denes ; Simon, Matthias ; Krischek, Boris ; Erson-Omay, E. Zeynep ; Henegariu, Octavian ; Carrión-Grant, Geneive ; Mishra-Gorur, Ketu ; Duran, Daniel ; Goldmann, Johanna E. ; Schramm, Johannes ; Goldbrunner, Roland ; Piepmeier, Joseph M. ; Vortmeyer, Alexander O. ; Günel, Jennifer Moliterno ; Bilgüvar, Kaya ; Yasuno, Katsuhito ; Young, Richard A. ; Günel, Murat

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la traduction de l'ARN messager, la protéine NRF2 favorise la prolifération des cellules d'une tumeur pancréatique

NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Chio, Iok In Christine ; Jafarnejad, Seyed Mehdi ; Ponz-Sarvise, Mariano ; Park, Youngkyu ; Rivera, Keith ; Palm, Wilhelm ; Wilson, John ; Sangar, Vineet ; Hao, Yuan ; Öhlund, Daniel ; Wright, Kevin ; Filippini, Dea ; Lee, Eun Jung ; Da Silva, Brandon ; Schoepfer, Christina ; Wilkinson, John Erby ; Buscaglia, Jonathan M ; DeNicola, Gina M ; Tiriac, Herve ; Hammell, Molly ; Crawford, Howard C ; Schmidt, Edward E ; Thompson, Craig B ; Pappin, Darryl J ; Sonenberg, Nahum ; Tuveson, David A

Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la protéine GOLM1, lliée à l'appareil de Golgi, dans la croissance et le processus métastatique d'un carcinome hépatocellulaire

GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis

Ye, Qing-Hai ; Zhu, Wen-Wei ; Zhang, Ju-Bo ; Qin, Yi ; Lu, Ming ; Lin, Guo-Ling ; Guo, Lei ; Zhang, Bo ; Lin, Zhen-Hai ; Roessler, Stephanie ; Forgues, Marshonna ; Jia, Hu-Liang ; Lu, Lu ; Zhang, Xiao-Fei ; Lian, Bao-Feng ; Xie, Lu ; Dong, Qiong-Zhu ; Tang, Zhao-You ; Wang, Xin Wei ; Qin, Lun-Xiu

The mechanism of cancer metastasis remains poorly understood. Using gene profiling of hepatocellular carcinoma (HCC) tissues, we have identified GOLM1 as a leading gene relating to HCC metastasis. GOLM1 expression is correlated with early recurrence, metastasis, and poor survival of HCC patients. Both gain- and loss-of-function studies determine that GOLM1 acts as a key oncogene by promoting HCC growth and metastasis. It selectively interacts with epidermal growth factor receptor (EGFR) and [...]

Menée à l'aide de modèles murins de myélome multiple, cette étude met en évidence des mécanismes par lesquels une enzyme, la thymidine phosphorylase, favorise la formation de métases osseuses

Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma

Liu, Huan ; Liu, Zhiqiang ; Du, Juan ; He, Jin ; Lin, Pei ; Amini, Behrang ; Starbuck, Michael W. ; Novane, Nora ; Shah, Jatin J. ; Davis, Richard E. ; Hou, Jian ; Gagel, Robert F. ; Yang, Jing

Bone tissue is built up by osteoblasts and broken down by osteoclasts in a balanced remodeling process. In metastatic cancer, however, the balance is tipped, leading to the formation of cancerous growths in the bone. Attempts to prevent metastasis have not been successful in the clinic; thus, Liu and colleagues set out in search of a new pathway to target. The authors found that an enzyme produced by myeloma cells, called thymidine phosphorylase (TP), suppressed osteoblast activity (new bone [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par les protéines PHD (prolyl hydroxylase) dans la formation de métastases pulmonaires

Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche

Clever, David ; Roychoudhuri, Rahul ; Constantinides, Michael G ; Askenase, Michael H ; Sukumar, Madhusudhanan ; Klebanoff, Christopher A ; Eil, Robert L ; Hickman, Heather D ; Yu, Zhiya ; Pan, Jenny H ; Palmer, Douglas C ; Phan, Anthony T ; Goulding, John ; Gattinoni, Luca ; Goldrath, Ananda W ; Belkaid, Yasmine ; Restifo, Nicholas P

Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T-cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung but powerfully licenses colonization by circulating tumor [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'interleukine 30 favorise la croissance et la progression d'une tumeur de cancer du sein triplement négatif

Interleukin-30 promotes breast cancer growth and progression

Airoldi, Irma ; Cocco, Claudia ; Sorrentino, Carlo ; Angelucci, Domenico ; Di Meo, Serena ; Manzoli, Lamberto ; Esposito, Silvia ; Ribatti, Domenico ; Bertolotto, Maria ; Iezzi, Laura ; Natoli, Clara ; Di Carlo, Emma

The inflammatory tissue microenvironment which promotes the development of breast cancer (BRCA) is not fully understood. Here we report a role for elevated IL-30 in supporting the BRCA cell viability and invasive migration. IL-30 was absent in normal mammary ducts, ductules and acini of histologically normal breast and scanty in the few stromal infiltrating leukocytes. In contrast, its IL-30 was expressed frequently in BRCA specimens where it was associated with triple-negative and HER2+ [...]

Cet article passe en revue les perspectives offertes par les nouvelles techniques d'ingénierie du génome pour induire des réarrangements chromosomiques dans des modèles précliniques de cancer

Somatic Engineering of Oncogenic Chromosomal Rearrangements: A Perspective

Maddalo, Danilo ; Ventura, Andrea

The ability to engineer specific mutations in mice has proven essential to advancing our understanding of the molecular basis of cancer. Chromosomal rearrangements, a common and clinically relevant class of cancer-causing mutations, have however remained difficult to faithfully recapitulate in vivo. The development of genetic tools for in vivo somatic genome editing has recently overcome this limitation and led to the generation of more sophisticated and accurate preclinical models of human [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes permettant, via des mutations activant la prolifération de cellules souches, de rendre compte du risque de cancer dans les divers organes

Multi-organ Mapping of Cancer Risk

Zhu, Liqin ; Finkelstein, David ; Gao, Culian ; Shi, Lei ; Wang, Yongdong ; Lopez-Terrada, Dolores ; Wang, Kasper ; Utley, Sarah ; Pounds, Stanley ; Neale, Geoffrey ; Ellison, David ; Onar-Thomas, Arzu ; Gilbertson, Richard James

Cancers are distributed unevenly across the body, but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used Cre-recombination of conditional lineage tracing, oncogene, and tumor suppressor alleles to define populations of stem and non-stem cells in mouse organs and test their life-long susceptibility to tumorigenesis. We show that tumor incidence is determined by the life-long generative capacity of mutated cells. [...]