Menée sur des échantillons tumoraux prélevés sur 958 patients atteints d'un cancer avancé et inclus dans des essais de phase I, cette étude analyse la fréquence des mutations du gène EGFR en fonction des diverses localisations tumorales

Aberrations in the epidermal growth factor receptor gene in 958 patients with diverse advanced tumors: implications for therapy

Wheler, J. J. ; Falchook, G. S. ; Tsimberidou, A. M. ; Hong, D. S. ; Naing, A. ; Piha-Paul, S. A. ; Chen, S. S. ; Fu, S. ; Stephen, B. ; Fok, J. Y. ; Janku, F. ; Kurzrock, R.

Background Epidermal growth factor receptor (EGFR) mutations are associated with the response to EGFR inhibitors in patients with non-small-cell lung cancer (NSCLC). We sought to investigate EGFR aberrations in patients with diverse advanced cancers. Patients and methods Patients referred to the phase I clinic were evaluated for the presence of EGFR mutations and response to therapy. Results EGFR aberrations were detected in 34 of 958 patients (3.5%). Though EGFR mutations were most frequent in [...]

A partir de données issues de 107 études d'hybridation génomique comparative et portant sur 8 227 échantillons tumoraux, cette étude analyse la fréquence de réarrangements génomiques massifs associés au phénomène de chromothripsis

Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes

Kim, Tae-Min ; Xi, Ruibin ; Luquette, Lovelace J ; Park, Richard W ; Johnson, Mark D ; Park, Peter J

A large database of copy number profiles from cancer genomes can facilitate the identification of recurrent chromosomal alterations that often contain key cancer-related genes. It can also be used to explore low-prevalence genomic events such as chromothripsis. In this study, we report an analysis of 8227 human cancer copy number profiles obtained from 107 array comparative genomic hybridization (CGH) studies. Our analysis reveals similarity of chromosomal arm-level alterations among [...]

A partir du séquençage complet du génome tumoral d'un patient atteint d'un lymphome de Burkitt, du séquençage de l'exome tumoral de 59 patients atteints d'un lymphome de Burkitt, et de données portant sur 94 patients atteints d'un lymphome diffus à grandes cellules B, cette étude met en évidence 70 gènes fréquemment mutés dans le lymphome de Burkitt et identifie des mutations du gène ID3 spécifiques de cette forme de lymphome

The genetic landscape of mutations in Burkitt lymphoma

Love, Cassandra ; Sun, Zhen ; Jima, Dereje ; Li, Guojie ; Zhang, Jenny ; Miles, Rodney ; Richards, Kristy L. ; Dunphy, Cherie H. ; Choi, William W. L. ; Srivastava, Gopesh ; Lugar, Patricia L. ; Rizzieri, David A. ; Lagoo, Anand S. ; Bernal-Mizrachi, Leon ; Mann, Karen P. ; Flowers, Christopher R. ; Naresh, Kikkeri N. ; Evens, Andrew M. ; Chadburn, Amy ; Gordon, Leo I. ; Czader, Magdalena B. ; Gill, Javed I. ; Hsi, Eric D. ; Greenough, Adrienne ; Moffitt, Andrea B. ; McKinney, Matthew ; Banerjee, Anjishnu ; Grubor, Vladimir ; Levy, Shawn ; Dunson, David B. ; Dave, Sandeep S.

Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt [...]

Menée initialement à partir d'échantillons prélevés sur 4 patients atteints d'un lymphome de Burkitt, puis validée sur une cohorte complémentaire de 53 patients, cette étude identifie de fréquentes mutations du gène ID3 en association avec la translocation IG-MYC

Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome [...]

Menée sur 36 lignées cellulaires et 744 échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude analyse la fréquence de mutations dans les gènes SMAD2, SMAD3 et SMAD4

SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer

Fleming, Nicholas ; Jorissen, Robert N. ; Mouradov, Dmitri ; Christie, Michael ; Sakthianandeswaren, Anuratha ; Palmieri, Michelle ; Day, Fiona ; Li, Shan ; Tsui, Cary ; Lipton, Lara ; Desai, Jayesh ; Jones, Ian T ; McLaughlin, Stephen ; Ward, Robyn L ; Hawkins, Nicholas J ; Ruszkiewicz, Andrew R ; Moore, James ; Zhu, Hong-Jian ; Mariadason, John M ; Burgess, Antony W ; Busam, Dana ; Zhao, Qi ; Strausberg, Robert L. ; Gibbs, Peter ; Sieber, Oliver M

Activation of the canonical transforming growth factor-β (TGF-β) signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members, TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2 and SMAD3, and analyzed for allelic loss by SNP microarray analysis. [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un neuroblastome, cette étude met en évidence des réarrangements du gène ALK associés à l'agressivité de la maladie

Characterization of rearrangements involving the ALK gene reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma

Cazes, Alex ; Louis-Brennetot, Caroline ; Mazot, Pierre ; Dingli, Florent ; Lombard, Berangere ; Boeva, Valentina ; Daveau, Romain ; Cappo, Julie ; Combaret, Valerie ; Schleiermacher, Gudrun ; Jouannet, Stephanie ; Ferrand, Sandrine ; Pierron, Gaëlle ; Barillot, Emmanuel ; Loew, Damarys ; Vigny, Marc ; Delattre, Olivier ; Janoueix-Lerosey, Isabelle

Activating mutations of the ALK gene have been identified in sporadic and familial cases of neuroblastoma (NB), a cancer of the peripheral nervous system, and are thought to be the primary mechanism of oncogenic activation of this receptor in this pediatric neoplasm. To address the possibility that ALK activation may occur through genomic rearrangements as detected in other cancers, we first took advantage of high-resolution array-CGH to search for ALK rearrangements in NB samples. Using [...]

Menée in vitro, cette étude montre que des mutations à l'interface du domaine kinase et du domaine d'homologie de la pleckstrine induisent l'activation de la protéine oncogénique AKT

Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

Parikh, Chaitali ; Janakiraman, Vasantharajan ; Wu, Wen-I ; Foo, Catherine K. ; Kljavin, Noelyn M. ; Chaudhuri, Subhra ; Stawiski, Eric ; Lee, Brian ; Lin, Jie ; Li, Hong ; Lorenzo, Maria N. ; Yuan, Wenlin ; Guillory, Joseph ; Jackson, Marlena ; Rondon, Jesus ; Franke, Yvonne ; Bowman, Krista K. ; Sagolla, Meredith ; Stinson, Jeremy ; Wu, Thomas D. ; Wu, Jiansheng ; Stokoe, David ; Stern, Howard M. ; Brandhuber, Barbara J. ; Lin, Kui ; Skelton, Nicholas J. ; Seshagiri, Somasekar

The protein kinase v-akt murine thymoma viral oncogene homolog (AKT), a key regulator of cell survival and proliferation, is frequently hyperactivated in human cancers. Intramolecular pleckstrin homology (PH) domain–kinase domain (KD) interactions are important in maintaining AKT in an inactive state. AKT activation proceeds after a conformational change that dislodges the PH from the KD. To understand these autoinhibitory interactions, we generated mutations at the PH–KD interface and found [...]

Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude suggère que l'accumulation de PDK1 dans le noyau des cellules tumorales favorise l'oncogenèse

Proliferative and Antiapoptotic Signaling Stimulated by Nuclear-Localized PDK1 Results in Oncogenesis

Kikani, Chintan K. ; Verona, Erik V. ; Ryu, Jiyoon ; Shen, Yanying ; Ye, Qingqing ; Zheng, Li ; Qian, Ziliang ; Sakaue, Hiroshi ; Nakamura, Kyoko ; Du, Jie ; Ji, Qunsheng ; Ogawa, Wataru ; Sun, Lu-Zhe ; Dong, Lily Q. ; Liu, Feng

Enhanced activation of phosphoinositide 3-kinase (PI3K) is a hallmark of many human tumors because it promotes cell proliferation and survival through several mechanisms. One of these mechanisms is the phosphorylation of the serine and threonine kinase Akt at the cytosolic side of the plasma membrane by phosphoinositide-dependent protein kinase 1 (PDK1), which is recruited and activated by binding to the phosphoinositides produced by PI3K. We previously demonstrated increased nuclear [...]

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel, en régulant le métabolisme mitochondrial, le gène FLCN joue un rôle de suppresseur de tumeurs dans le syndrome de Birt-Hogg-Dubé, une maladie héréditaire caractérisée par des lésions cutanées, des tumeurs rénales et des kystes pulmonaires

Regulation of Mitochondrial Oxidative Metabolism by Tumor Suppressor FLCN

Hasumi, Hisashi ; Baba, Masaya ; Hasumi, Yukiko ; Huang, Ying ; Oh, Hyoungbin ; Hughes, Robert M. ; Klein, Mara E. ; Takikita, Shoichi ; Nagashima, Kunio ; Schmidt, Laura S. ; Linehan, W. Marston

Background Birt-Hogg-Dubé (BHD) syndrome is a hereditary hamartoma syndrome that predisposes patients to develop hair follicle tumors, lung cysts, and kidney cancer. Genetic studies of BHD patients have uncovered the causative gene, FLCN, but its function is incompletely understood. Methods Mice with conditional alleles of FLCN and/or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), a transcriptional coactivator that regulates mitochondrial biogenesis, were [...]

Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein triplement négatif, cette étude met en évidence le rôle joué par une enzyme, la lactate déshydrogénase B, dans cette forme de cancer du sein

An Integrated Genomic Screen Identifies LDHB as an Essential Gene for Triple-Negative Breast Cancer

McCleland, Mark L. ; Adler, Adam S. ; Shang, Yonglei ; Hunsaker, Thomas ; Truong, Tom ; Peterson, David ; Torres, Eric ; Li, Li ; Haley, Benjamin ; Stephan, Jean-Philippe ; Belvin, Marcia ; Hatzivassiliou, Georgia ; Blackwood, Elizabeth M. ; Corson, Laura ; Evangelista, Marie ; Zha, Jiping ; Firestein, Ron

Breast cancer has been redefined into three clinically relevant subclasses: (i) estrogen/progesterone receptor positive (ER+/PR+), (ii) HER2/ERRB2 positive, and (iii) those lacking expression of all three markers (triple negative or basal-like). While targeted therapies for ER+/PR+ and HER2+ tumors have revolutionized patient treatment and increased lifespan, an urgent need exists for identifying novel targets for triple-negative breast cancers. Here, we used integrative genomic analysis to [...]

Cet article passe en revue les travaux récents sur le rôle de la voie de signalisation de la kynurénine, un métabolite de l'acide aminé tryptophane, dans la pathogenèse des tumeurs cérébrales

The Kynurenine Pathway in Brain Tumor Pathogenesis

Adams, Seray ; Braidy, Nady ; Bessesde, Alban ; Brew, Bruce J. ; Grant, Ross ; Teo, Charlie ; Guillemin, Gilles J.

Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of l-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel l'expression de l'enzyme PLD1 dans le micro-environnement tumoral favorise la croissance tumorale et le processus métastatique

Key Roles for the Lipid Signaling Enzyme Phospholipase D1 in the Tumor Microenvironment During Tumor Angiogenesis and Metastasis

Chen, Qin ; Hongu, Tsunaki ; Sato, Takanobu ; Zhang, Yi ; Ali, Wahida ; Cavallo, Julie-Ann ; van der Velden, Adrianus ; Tian, Huasong ; Di Paolo, Gilbert ; Nieswandt, Bernhard ; Kanaho, Yasunori ; Frohman, Michael A.

Angiogenesis inhibitors, which target tumor cells, confer only short-term benefits on tumor growth. We report that ablation of the lipid signaling enzyme phospholipase D1 (PLD1) in the tumor environment compromised the neovascularization and growth of tumors. PLD1 deficiency suppressed the activation of Akt and mitogen-activated protein kinase signaling pathways by vascular endothelial growth factor in vascular endothelial cells, resulting in decreased integrin-dependent cell adhesion to, and [...]

Menée à l'aide de xénogreffes, cette étude évalue la capacité d'un modèle murin à reproduire le processus métastatique d'un mélanome humain

Human Melanoma Metastasis in NSG Mice Correlates with Clinical Outcome in Patients

Quintana, Elsa ; Piskounova, Elena ; Shackleton, Mark ; Weinberg, Daniel ; Eskiocak, Ugur ; Fullen, Douglas R. ; Johnson, Timothy M. ; Morrison, Sean J.

Studies of human cancer metastasis have been limited by a lack of experimental assays in which cancer cells from patients metastasize in vivo in a way that correlates with clinical outcome. This makes it impossible to study intrinsic differences in the metastatic properties of cancers from different patients. We recently developed an assay in which human melanomas readily engraft in nonobese diabetic/severe combined immunodeficient interleukin-2 receptor-γ chain null (NSG) mice. We show that [...]

Menée in vivo, cette étude identifie trois micro-ARNs qui, en ciblant l'apolipoprotéine ApoE, favorisent le processus métastatique d'un mélanome

Convergent Multi-miRNA Targeting of ApoE Drives LRP1/LRP8-Dependent Melanoma Metastasis and Angiogenesis

Pencheva, Nora ; Tran, Hien ; Buss, Colin ; Huh, Doowon ; Drobnjak, Marija ; Busam, Klaus ; Tavazoie, Sohail F

Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en se liant à la glycoprotéine de surface EMMPRIN, la protéine S100A9 favorise le processus métastatique d'un mélanome

S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis

Hibino, Toshihiko ; Sakaguchi, Masakiyo ; Miyamoto, Shoko ; Yamamoto, Mami ; Motoyama, Akira ; Hosoi, Junichi ; Shimokata, Tadashi ; Ito, Tomonobu ; Tsuboi, Ryoji ; Huh, Nam-ho

The calcium binding proteins S100A8 and S100A9 can dimerize to form calprotectin, the release of which during tissue damage has been implicated in inflammation and metastasis. However, receptor(s) mediating the physiological and pathophysiological effects of this damage-associated 'danger signal' are uncertain. In this study, searching for candidate calprotectin receptors by affinity isolation-mass spectrometry, we identified the cell surface glycoprotein EMMPRIN/BASIGIN (CD147/BSG). EMMPRIN [...]

Menée sur une cohorte de 149 patients atteints d'un cancer du poumon et 123 témoins, cette étude évalue la capacité d'une nouvelle approche pour identifier des antigènes spécifiques des tumeurs susceptibles de servir de cibles cliniques ou immunologiques

An integrated genome-wide approach to discover tumor specific antigens as potential immunological and clinical targets in cancer

Xu, Qing-Wen ; Zhao, Wei ; Wang, Yue ; Sartor, Maureen A ; Han, Dong-Mei ; Deng, Jixin ; Ponnala, Rakesh ; Yang, Jiang-Ying ; Zhang, Qing-Yun ; Liao, Guo-Qing ; Qu, Yi-Mei ; Li, Lu ; Liu, Fang-Fang ; Zhao, Hong-Mei ; Yin, Yan-Hui ; Chen, Wei-Feng ; Zhang, Yu ; Wang, Xiaosong

Tumor-specific antigens (TSAs) are central elements in the immune control of cancers. To systematically explore the TSA genome, we developed a computational technology called Heterogeneous Expression Profile Analysis (HEPA), which can identify genes relatively uniquely expressed in cancer cells in contrast to normal somatic tissues. Rating human genes by their HEPA score enriched for clinically useful TSA genes, nominating candidate targets whose tumor-specific expression was verified by [...]