Menée sur une cohorte de 32 patients atteints d'une leucémie prolymphocytaire T, cette étude identifie, pour 11 d'entre eux, la présence de mutations activant le gène JAK3

Recurrent mutation of JAK3 in T-cell prolymphocytic leukemia

Bergmann, Anke K. ; Schneppenheim, Sina ; Seifert, Marc ; Betts, Matthew J. ; Haake, Andrea ; Lopez, Cristina ; Maria Murga Penas, Eva ; Vater, Inga ; Jayne, Sandrine ; Dyer, Martin J. S. ; Schrappe, Martin ; Dührsen, Ulrich ; Ammerpohl, Ole ; Russell, Robert B. ; Küppers, Ralf ; Dürig, Jan ; Siebert, Reiner

T-cell prolymphocytic leukemia (T-PLL) is an aggressive post-thymic T-cell malignancy characterized by the recurrent inv(14)(q11q32)/t(14;14)(q11;q32) or t(X;14)(q28;q11) leading to activation of either the TCL1 or MTCP1 gene, respectively. However, these primary genetic events are insufficient to drive leukemogenesis. Recently, activating mutations in JAK3 have been identified in other T-cell malignancies. Since JAK3 is essential for T-cell maturation, we analyzed a cohort of 32 T-PLL patients [...]

Menée in vitro et in vivo, cette étude montre que la perte de larges régions du chromosome 10, un phénomène fréquent dans les mélanomes, entraîne l'absence d'expression de plusieurs gènes suppresseurs de tumeurs, notamment le gène Ablim1

Chromosome 10, Frequently Lost in Human Melanoma, Encodes Multiple Tumor Suppressive Functions

Kwong, Lawrence N. ; Chin, Lynda

Although many DNA aberrations in melanoma have been well characterized, including focal amplification and deletions of oncogenes and tumor suppressors, broad regions of chromosomal gain and loss are less well understood. One possibility is that these broad events are a consequence of collateral damage from targeting single loci. Another possibility is that the loss of large regions permits simultaneous inactivation of multiple tumor suppressors, by broadly decreasing the resident gene dosage [...]

Menée sur des échantillons prélevés sur 429 patientes atteintes d'un carcinome de l'ovaire et sur 557 témoins, cette étude met en évidence le paysage des mutations somatiques et constitutionnelles, puis identifie les voies de signalisation significativement modifiées par ces mutations

Integrated analysis of germline and somatic variants in ovarian cancer

Kanchi, Krishna L. ; Johnson, Kimberly J. ; Lu, Charles ; McLellan, Michael D. ; Leiserson, Mark D. M. ; Wendl, Michael C. ; Zhang, Qunyuan ; Koboldt, Daniel C. ; Xie, Mingchao ; Kandoth, Cyriac ; McMichael, Joshua F. ; Wyczalkowski, Matthew A. ; Larson, David E. ; Schmidt, Heather K. ; Miller, Christopher A. ; Fulton, Robert S. ; Spellman, Paul T. ; Mardis, Elaine R. ; Druley, Todd E. ; Graubert, Timothy A. ; Goodfellow, Paul J. ; Raphael, Benjamin J. ; Wilson, Richard K. ; Ding, Li

We report the first large-scale exome-wide analysis of the combined germline–somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In [...]

Menée sur des échantillons de tissu tumoral et de tissu sain adjacent prélevés sur 10 patients atteints d'un adénocarcinome du poumon de stade I, cette étude de séquençage du génome et de l'exome entiers identifie des mutations somatiques de plusieurs gènes

Identification of somatic alterations in stage I lung adenocarcinomas by next-generation sequencing

Zhao, Yuda ; Yang, Jie ; Chen, Zhaoli ; Gao, Zhibo ; Zhou, Fang ; Li, Xiangchun ; Li, Jiagen ; Shi, Susheng ; Feng, Xiaoli ; Sun, Nan ; Yao, Ran ; Zhou, Chengcheng ; Chang, Sheng ; Li, Miao ; Zhou, Yong ; Li, Lin ; Zhang, Xiuqing ; He, Jie

Adenocarcinoma is the most common type of lung cancer. Somatic mutations in the early stage of this disease have a tight relationship with tumor initiation and potentially activate downstream pathways that are implicated in tumor progression. In this study, we performed whole genome and exome sequencing of tumor and adjacent normal tissue from 10 patients with stage I lung adenocarcinoma. EGFR (4/10 tumors), BCHE (3/10), and TP53 (2/10) were identified recurrently with validated tumor-specific [...]

Menée sur des échantillons de tumeurs métastatiques prélevés à l'autopsie sur 11 patientes décédées d'un cancer du sein, cette étude met en évidence une plus grande hétérogénéité génétique et phénotypique des métastases par rapport aux tumeurs primitives

Genetic and phenotypic diversity in breast tumor metastases

Almendro, Vanessa ; Kim, HeeJung ; Cheng, Yu-Kang ; Gonen, Mithat ; Itzkovitz, Shalev ; Argani, Pedram ; van Oudenaarden, Alexander ; Sukumar, Saraswati ; Michor, Franziska ; Polyak, Kornelia

Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance our knowledge of how cancer cell populations change during metastatic progression is limited. Here we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immuno-FISH in intact tissue sections of distant [...]

Cet article passe en revue les travaux récents sur les fonctions exercées par les protéines de la superfamille des cadhérines dans le développement et la progression de divers types de cancer

Beyond E-cadherin: roles of other cadherin superfamily members in cancer

van Roy, Frans

Loss of cadherin 1 (CDH1; also known as epithelial cadherin (E-cadherin)) is used for the diagnosis and prognosis of epithelial cancers. However, it should not be ignored that the superfamily of transmembrane cadherin proteins encompasses more than 100 members in humans, including other classical cadherins, numerous protocadherins and cadherin-related proteins. Elucidation of their roles in suppression versus initiation or progression of various tumour types is a young but fascinating field of [...]

Menée à l'aide d'un modèle murin de cancer du poumon induit par la mutation G12D du gène KRas, cette étude met en évidence des mécanismes par lesquels, sous la régulation du gène Atg5, l'autophagie est susceptible d'accélérer la progression tumorale ou de réprimer les premières phases de l'oncogenèse

A dual role for autophagy in a murine model of lung cancer

Rao, Shuan ; Tortola, Luigi ; Perlot, Thomas ; Wirnsberger, Gerald ; Novatchkova, Maria ; Nitsch, Roberto ; Sykacek, Peter ; Frank, Lukas ; Schramek, Daniel ; Komnenovic, Vukoslav ; Sigl, Verena ; Aumayr, Karin ; Schmauss, Gerald ; Fellner, Nicole ; Handschuh, Stephan ; Glösmann, Martin ; Pasierbek, Pawel ; Schlederer, Michaela ; Resch, Guenter P. ; Ma, Yuting ; Yang, Heng ; Popper, Helmuth ; Kenner, Lukas ; Kroemer, Guido ; Penninger, Josef M.

Autophagy is a mechanism by which starving cells can control their energy requirements and metabolic states, thus facilitating the survival of cells in stressful environments, in particular in the pathogenesis of cancer. Here we report that tissue-specific inactivation of Atg5, essential for the formation of autophagosomes, markedly impairs the progression of KRasG12D-driven lung cancer, resulting in a significant survival advantage of tumour-bearing mice. Autophagy-defective lung cancers [...]

Menée sur des échantillons tumoraux prélevés sur 231 patientes atteintes d'un cancer du sein, cette étude met en évidence des différences d'expression des récepteurs aux estrogènes selon que le cancer est de type canalaire ou lobulaire

Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer

Huang, Bo ; Omoto, Yoko ; Iwase, Hirotaka ; Yamashita, Hiroko ; Toyama, Tatsuya ; Coombes, Raoul Charles ; Filipovic, Aleksandra ; Warner, Margaret ; Gustafsson, Jan-Åke

The role of estrogen receptor (ER) α as a target in treatment of breast cancer is clear, but those of ERβ1 and ERβ2 in the breast remain unclear. We have examined expression of all three receptors in surgically excised breast samples from two archives: (i): 187 invasive ductal breast cancer from a Japanese study; and (ii) 20 lobular and 24 ductal cancers from the Imperial College. Samples contained normal areas, areas of hyperplasia, and in situ and invasive cancer. In the normal areas, ERα was [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en exprimant l'enzyme IDO, les cellules souches mésenchymateuses régulent la prolifération des lymphocytes T dans le micro-environnement tumoral

Mesenchymal Stem Cells Employ IDO to Regulate Immunity in Tumor Microenvironment

Ling, Weifang ; Zhang, Jimin ; Yuan, Zengrong ; Ren, Guangwen ; Zhang, Liying ; Chen, Xiaodong ; Rabson, Arnold B ; Roberts, Arthur I ; Wang, Ying ; Shi, Yufang

Mesenchymal stem cells (MSCs) are present in most, if not all, tissues and are believed to contribute to tissue regeneration and the tissue immune microenvironment. Murine MSCs exert immunosuppressive effects through production of the nitric oxide synthase iNOS, while human MSCs utilize indoleamine 2,3-dioxygenase (IDO). Thus, studies of MSC-mediated immunomodulation in mice may not be informative in the setting of human disease, although this critical difference has been mainly ignored. To [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en induisant une transition épithélio-mésenchymateuse, la protéine PTHrP favorise le processus métastatique d'un cancer de la prostate

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

Ongkeko, Weg M. ; Burton, Doug ; Kiang, Alan ; Abhold, Eric ; Kuo, Selena Z. ; Rahimy, Elham ; Yang, Meng ; Hoffman, Robert M. ; Wang-Rodriguez, Jessica ; Deftos, Leonard J.

Parathyroid hormone-related protein (PTHrP) possesses a variety of physiological and developmental functions and is also known to facilitate the progression of many common cancers, notably their skeletal invasion, primarily by increasing bone resorption. The purpose of this study was to determine whether PTHrP could promote epithelial-to-mesenchymal transition (EMT), a process implicated in cancer stem cells that is critically involved in cancer invasion and metastasis. EMT was observed in DU [...]

Cette étude présente une nouvelle méthode permettant d'établir rapidement des modèles murins génétiquement modifiés pour mener des études précliniques de validation d'une cible thérapeutique, puis illustre son intérêt en identifiant le gène MycL1 comme cible potentielle dans le cancer du poumon à petites cellules

Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells

Huijbers, Ivo J. ; Bin Ali, Rahmen ; Pritchard, Colin ; Cozijnsen, Miranda ; Kwon, Min-Chul ; Proost, Natalie ; Song, Ji-Ying ; de Vries, Hilda ; Badhai, Jitendra ; Sutherland, Kate ; Krimpenfort, Paul ; Michalak, Ewa M. ; Jonkers, Jos ; Berns, Anton

Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome [...]

Cet article passe en revue les leçons à tirer, pour la compréhension de divers types de cancer, des travaux récents sur la biologie des phéochromocytomes et des paragangliomes

Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity

Dahia, Patricia L. M.

The neuroendocrine tumours pheochromocytomas and paragangliomas carry the highest degree of heritability in human neoplasms, enabling genetic alterations to be traced to clinical phenotypes through their transmission in families. Mutations in more than a dozen distinct susceptibility genes have implicated multiple pathways in these tumours, offering insights into kinase downstream signalling interactions and hypoxia regulation, and uncovering links between metabolism, epigenetic remodelling and [...]