Menée initialement à partir d'échantillons de tissu tumoral et de tissu sain prélevés sur 25 patients atteints d'une tumeur surrénalienne produisant du cortisol, puis sur 13 patients complémentaires, cette étude identifie un ensemble de mutations somatiques, notamment dans le gène PRKACA

Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors

Goh, Gerald ; Scholl, Ute I. ; Healy, James M. ; Choi, Murim ; Prasad, Manju L. ; Nelson-Williams, Carol ; Kuntsman, John W. ; Korah, Reju ; Suttorp, Anna-Carinna ; Dietrich, Dimo ; Haase, Matthias ; Willenberg, Holger S. ; Stalberg, Peter ; Hellman, Per ; Akerstrom, Goran ; Bjorklund, Peyman ; Carling, Tobias ; Lifton, Richard P.

Adrenal tumors autonomously producing cortisol cause Cushing's syndrome. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (

Menée initialement à partir d'échantillons tumoraux prélevés sur 45 patients atteints d'un carcinome corticosurrénalien, puis sur une cohorte complémentaire de 77 patients, cette étude identifie, sur la base d'une analyse génomique intégrée, deux sous-groupes associés à une forme agressive ou indolente de la maladie

Integrated genomic characterization of adrenocortical carcinoma

Assie, Guillaume ; Letouzé, Eric ; Fassnacht, Martin ; Jouinot, Anne ; Luscap, Windy ; Barreau, Olivia ; Omeiri, Hanin ; Rodriguez, Stephanie ; Perlemoine, Karine ; Rene-Corail, Fernande ; Elarouci, Nabila ; Sbiera, Silviu ; Kroiss, Matthias ; Allolio, Bruno ; Waldmann, Jens ; Quinkler, Marcus ; Mannelli, Massimo ; Mantero, Franco ; Papathomas, Thomas ; De Krijger, Ronald ; Tabarin, Antoine ; Kerlan, Veronique ; Baudin, Eric ; Tissier, Frederique ; Dousset, Bertrand ; Groussin, Lionel ; Amar, Laurence ; Clauser, Eric ; Bertagna, Xavier ; Ragazzon, Bruno ; Beuschlein, Felix ; Libe, Rossella ; de Reyniès, Aurélien ; Bertherat, Jérôme

Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 [...]

Menée sur 596 patients pédiatriques atteints d'une leucémie myéloïde aiguë, cette étude analyse les anomalies du caryotype en association avec les caractéristiques cliniques des patients

Ploidy and clinical characteristics of childhood acute myeloid leukemia: A NOPHO-AML study

Sandahl, Julie Damgaard ; Kjeldsen, Eigil ; Abrahamsson, Jonas ; Ha, Shau-Yin ; Heldrup, Jesper ; Jahnukainen, Kirsi ; Jónsson, Ólafur G. ; Lausen, Birgitte ; Palle, Josefine ; Zeller, Bernward ; Forestier, Erik ; Hasle, Henrik

We report the first large series (n = 596) of pediatric acute myeloid leukemia (AML) focusing on modal numbers (MN) from the population-based NOPHO-AML trials. Abnormal karyotypes were present in 452 cases (76%) and numerical aberrations were present in 40% (n = 237) of all pediatric AML. Among patients with an abnormal karyotype, the MN 46 was most common (n = 251; 56%) of which 36 (8%) were pseudodiploid with numerical aberrations, followed by MN 47 (n = 80; 18%) and MN 43–45 (n = 48; 8%). No [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via la surexpression du gène HMGN1, une trisome 21 favorise le développement d'une leucémie aiguë lymphoblastique à cellules B

Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation

Lane, Andrew A. ; Chapuy, Bjoern ; Lin, Charles Y. ; Tivey, Trevor ; Li, Hubo ; Townsend, Elizabeth C. ; van Bodegom, Diederik ; Day, Tovah A. ; Wu, Shuo-Chieh ; Liu, Huiyun ; Yoda, Akinori ; Alexe, Gabriela ; Schinzel, Anna C. ; Sullivan, Timothy J. ; Malinge, Sebastien ; Taylor, Jordan E. ; Stegmaier, Kimberly ; Jaffe, Jacob D. ; Bustin, Michael ; te Kronnie, Geertruy ; Izraeli, Shai ; Harris, Marian H. ; Stevenson, Kristen E. ; Neuberg, Donna ; Silverman, Lewis B. ; Sallan, Stephen E. ; Bradner, James E. ; Hahn, William C. ; Crispino, John D. ; Pellman, David ; Weinstock, David M.

Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs. Yet the mechanistic links between chromosome 21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chromosome 21q22 confers mouse progenitor B cell self renewal in vitro, maturation defects in vivo and B-ALL with either the BCR-ABL fusion protein or CRLF2 with [...]

A partir de données publiées portant sur 241 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un mélanome, cette méta-analyse identifie un ensemble de mutations somatiques susceptibles d'inciter à la prescription d'une thérapie ciblée existante ou émergente

A meta-analysis of somatic mutations from next generation sequencing of 241 melanomas: a road map for the study of genes with potential clinical relevance

Xia, Junfeng ; Jia, Peilin ; Hutchinson, Katherine E. ; Dahlman, Kimberly B ; Johnson, Douglas B ; Sosman, Jeffrey ; Pao, William ; Zhao, Zhongming

Next generation sequencing (NGS) has been used to characterize the overall genomic landscape of melanomas. Here, we systematically examined mutations from recently published melanoma NGS data involving 241 paired tumor-normal samples to identify potentially clinically relevant mutations. Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, [...]

Menée sur 5 125 échantillons tumoraux prélevés sur des patients chinois atteints d'un cancer du poumon non à petites cellules, cette étude analyse la fréquence des mutations somatiques des gènes EGFR, KRAS, BRAF et PIK3CA en fonction du sexe et du statut tabagique des patients

Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts

Li, S. ; Li, L. ; Zhu, Y. ; Huang, C. ; Qin, Y. ; Liu, H. ; Ren-Heidenreich, L. ; Shi, B. ; Ren, H. ; Chu, X. ; Kang, J. ; Wang, W. ; Xu, J. ; Tang, K. ; Yang, H. ; Zheng, Y. ; He, J. ; Yu, G. ; Liang, N.

Background: Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study. Methods: Five thousand one hundred and twenty-five NSCLC patients’ pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels le gène p53 exerce une fonction de suppresseur de tumeurs

Unravelling mechanisms of p53-mediated tumour suppression

Bieging, Kathryn T. ; Mello, Stephano Spano ; Attardi, Laura D.

p53 is a crucial tumour suppressor that responds to diverse stress signals by orchestrating specific cellular responses, including transient cell cycle arrest, cellular senescence and apoptosis, which are all processes associated with tumour suppression. However, recent studies have challenged the relative importance of these canonical cellular responses for p53-mediated tumour suppression and have highlighted roles for p53 in modulating other cellular processes, including metabolism, stem cell [...]

Cet article passe en revue les travaux récents sur le rôle de la signalisation KRAS dans les adénocarcinomes canalaires du pancréas

Oncogenic KRAS signalling in pancreatic cancer

Eser, S. ; Schnieke, A. ; Schneider, G. ; Saur, D.

Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel [...]

Menée à l'aide d'un modèle murin de glioblastome, cette étude met en évidence des mécanismes par lesquels, via une accumulation du facteur HIF-1α dans les cellules endothéliales, la phosphorylation d'une profiline (Pfn-1) favorise la progression tumorale

Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation

Fan, Yi ; Potdar, Alka A. ; Gong, Yanqing ; Eswarappa, Sandeepa M. ; Donnola, Shannon ; Lathia, Justin D. ; Hambardzumyan, Dolores ; Rich, Jeremy N. ; Fox, Paul L.

The tumour vascular microenvironment supports tumorigenesis not only by supplying oxygen and diffusible nutrients but also by secreting soluble factors that promote tumorigenesis. Here we identify a feedforward mechanism in which endothelial cells (ECs), in response to tumour-derived mediators, release angiocrines driving aberrant vascularization and glioblastoma multiforme (GBM) progression through a hypoxia-independent induction of hypoxia-inducible factor (HIF)-1α. Phosphorylation of [...]

Menée à partir de données issues du projet "The Cancer Genome Atlas", puis in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels des anomalies d'expression du gène Notch3 favorisent la progression d'un cancer de l'ovaire

Notch3 Pathway Alterations in Ovarian Cancer

Hu, Wei ; Liu, Tao ; Ivan, Cristina ; Sun, Yunjie ; Huang, Jie ; Mangala, Lingegowda S. ; Miyake, Takahito ; Dalton, Heather J. ; Pradeep, Sunila ; Rupaimoole, Rajesh ; Previs, Rebecca A. ; Han, Hee-Dong ; Bottsford-Miller, Justin ; Zand, Behrouz ; Kang, Yu ; Pecot, Chad V. ; Nick, Alpa M. ; Wu, Sherry Y. ; Lee, Ju-Seog ; Sehgal, Vasudha ; Ram, Prahlad ; Liu, Jinsong ; Tucker, Susan L ; Lopez-Berestein, Gabriel ; Baggerly, Keith A. ; Coleman, Robert L. ; Sood, Anil K.

Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biological mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited OvCa growth and [...]

Menée sur des lignées cellulaires de cancer du sein, cette étude montre que l'induction d'une transition épithélio-mésenchymateuse n'a pas d'incidence sur les capacités des cellules souches cancéreuses à former des tumeurs

Tumour-initiating capacity is independent of epithelial-mesenchymal transition status in breast cancer cell lines

Xie, G. ; Ji, A. ; Yuan, Q. ; Jin, Z. ; Yuan, Y. ; Ren, C. ; Guo, Z. ; Yao, Q. ; Yang, K. ; Lin, X. ; Chen, L.

Background: Epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs) are considered to be crucial for cancer biology. The purpose of this study was to determine whether EMT directly led to the acquisition of tumour-initiating capacity in breast cancer cell lines. Methods: Epithelial–mesenchymal transition was induced in five breast cancer cell lines and one normal breast cell line by EMT-related cytokine stimulation. Mesenchymal–epithelial transition (MET) was induced by stably [...]

Menée sur des lignées cellulaires et à l'aide de données cliniques, cette étude met en évidence le rôle joué par une métalloprotéase matricielle membranaire dans le processus invasif d'un cancer du sein

Control of MT1-MMP transport by atypical PKC during breast-cancer progression

Rossé, Carine ; Lodillinsky, Catalina ; Fuhrmann, Laetitia ; Nourieh, Maya ; Monteiro, Pedro ; Irondelle, Marie ; Lagoutte, Emilie ; Vacher, Sophie ; Waharte, François ; Paul-Gilloteaux, Perrine ; Romao, Maryse ; Sengmanivong, Lucie ; Linch, Mark ; van Lint, Johan ; Raposo, Graça ; Vincent-Salomon, Anne ; Bièche, Ivan ; Parker, Peter J. ; Chavrier, Philippe

Dissemination of carcinoma cells requires the pericellular degradation of the extracellular matrix, which is mediated by membrane type 1-matrix metalloproteinase (MT1-MMP). In this article, we report a co–up-regulation and colocalization of MT1-MMP and atypical protein kinase C iota (aPKCι) in hormone receptor-negative breast tumors in association with a higher risk of metastasis. Silencing of aPKC in invasive breast-tumor cell lines impaired the delivery of MT1-MMP from late endocytic storage [...]

Menée à l'aide d'un modèle murin, cette étude montre qu'une tumeur invasive de la vessie se développe à partir de cellules souches exprimant Shh dans la membrane basale de l'urothélium

Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma

Shin, Kunyoo ; Lim, Agnes ; Odegaard, Justin I. ; Honeycutt, Jared D. ; Kawano, Sally ; Hsieh, Michael H. ; Beachy, Philip A.

Understanding how malignancies arise within normal tissues requires identification of the cancer cell of origin and knowledge of the cellular and tissue dynamics of tumour progression. Here we examine bladder cancer in a chemical carcinogenesis model that mimics muscle-invasive human bladder cancer. With no prior bias regarding genetic pathways or cell types, we prospectively mark or ablate cells to show that muscle-invasive bladder carcinomas arise exclusively from Sonic hedgehog [...]

Cet article présente des recommandations pour réduire le taux de faux positifs dans l'analyse des variants de séquence génomique associés à une maladie humaine

Guidelines for investigating causality of sequence variants in human disease

MacArthur, D. G. ; Manolio, T. A. ; Dimmock, D. P. ; Rehm, H. L. ; Shendure, J. ; Abecasis, G. R. ; Adams, D. R. ; Altman, R. B. ; Antonarakis, S. E. ; Ashley, E. A. ; Barrett, J. C. ; Biesecker, L. G. ; Conrad, D. F. ; Cooper, G. M. ; Cox, N. J. ; Daly, M. J. ; Gerstein, M. B. ; Goldstein, D. B. ; Hirschhorn, J. N. ; Leal, S. M. ; Pennacchio, L. A. ; Stamatoyannopoulos, J. A. ; Sunyaev, S. R. ; Valle, D. ; Voight, B. F. ; Winckler, W. ; Gunter, C.

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges [...]

Cet article passe en revue les perspectives offertes par les travaux en écologie et en dynamique des populations pour modéliser le comportement des tumeurs et de leur micro-environnement

Turning ecology and evolution against cancer

Korolev, Kirill S. ; Xavier, Joao B. ; Gore, Jeff

The fight against cancer has drawn researchers from a wide variety of disciplines, ranging from molecular biology to physics, but the perspective of an ecological theorist has been mostly overlooked. By thinking about the cells that make up a tumour as an endangered species, cancer vulnerabilities become more apparent. Studies in conservation biology and microbial experiments indicate that extinction is a complex phenomenon, which is often driven by the interaction of ecological and [...]

Menée à l'aide de lignées cellulaires, d'échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas et de xénogreffes, cette étude met en évidence des modifications d'expression de gènes dans les tumeurs des modèles murins xénogreffés par rapport aux tumeurs primitives

Transcriptional dissection of pancreatic tumors engrafted in mice

Martinez-Garcia, Raquel ; Juan, David ; Rausell, Antonio ; Munoz, Manuel ; Banos, Natalia ; Menendez, Camino ; Lopez-Casas, Pedro ; Rico, Daniel ; Valencia, Alfonso ; Hidalgo, Manuel

BACKGROUND:Engraftment of primary pancreas ductal adenocarcinomas (PDAC) in mice to generate patient-derived xenograft (PDX) models is a promising platform for biological and therapeutic studies in this disease. However, these models are still incompletely characterized. Here, we measured the impact of the murine tumor environment on the gene expression of the engrafted human tumoral cells. METHODS:We have analyzed gene expression profiles from 35 new PDX models and compared them with [...]