Menée à l'aide d'une technique de séquençage de prochaine génération sur 189 gènes associés au cancer dans 29 échantillons prélevés sur des patients pédiatriques atteints d'un lymphome de Burkitt, cette étude identifie de nouvelles altérations génomiques, notamment dans un gène impliqué dans le remodelage de la chromatine et un gène exerçant une fonction anti-apoptotique

Targeted genomic sequencing of pediatric Burkitt lymphoma identifies recurrent alterations in anti-apoptotic and chromatin-remodeling genes

Giulino-Roth, Lisa ; Wang, Kai ; MacDonald, Theresa Y. ; Mathew, Susan ; Tam, Yifang ; Cronin, Maureen T. ; Palmer, Gary ; Lucena-Silva, Norma ; Pedrosa, Francisco ; Pedrosa, Marcia ; Teruya-Feldstein, Julie ; Bhagat, Govind ; Alobeid, Bachir ; Leoncini, Lorenzo ; Bellan, Cristiana ; Rogena, Emily ; Pinkney, Kerice A. ; Rubin, Mark A. ; Ribeiro, Raul C. ; Yelensky, Roman ; Tam, Wayne ; Stephens, Philip J. ; Cesarman, Ethel

To ascertain the genetic basis of pediatric Burkitt lymphoma (pBL) we performed clinical-grade next generation sequencing (NGS) of 189 cancer-related genes on 29 formalin-fixed paraffin embedded (FFPE) primary pBL samples. Ninety percent of cases had at least one mutation or genetic alteration, most commonly involving MYC and TP53. EBV(-) cases were more likely than EBV(+) cases to have multiple mutations (p<0.0001). Alterations in tumor-related genes not previously described in BL were [...]

Menée sur 99 échantillons prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas et à l'aide d'un modèle murin, cette étude identifie de fréquentes mutations somatiques de gènes traditionnellement associés à la régulation du guidage axonal

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Biankin, Andrew V. ; Waddell, Nicola ; Kassahn, Karin S. ; Gingras, Marie-Claude ; Muthuswamy, Lakshmi B. ; Johns, Amber L. ; Miller, David K. ; Wilson, Peter J. ; Patch, Ann-Marie ; Wu, Jianmin ; Chang, David K. ; Cowley, Mark J. ; Gardiner, Brooke B. ; Song, Sarah ; Harliwong, Ivon ; Idrisoglu, Senel ; Nourse, Craig ; Nourbakhsh, Ehsan ; Manning, Suzanne ; Wani, Shivangi ; Gongora, Milena ; Pajic, Marina ; Scarlett, Christopher J. ; Gill, Anthony J. ; Pinho, Andreia V. ; Rooman, Ilse ; Anderson, Matthew ; Holmes, Oliver ; Leonard, Conrad ; Taylor, Darrin ; Wood, Scott ; Xu, Christina ; Nones, Katia ; Lynn Fink, J. ; Christ, Angelika ; Bruxner, Tim ; Cloonan, Nicole ; Kolle, Gabriel ; Newell, Felicity ; Pinese, Mark ; Scott Mead, R. ; Humphris, Jeremy L. ; Kaplan, Warren ; Jones, Marc D. ; Colvin, Emily K. ; Nagrial, Adnan M. ; Humphrey, Emily S. ; Chou, Angela ; Chin, Venessa T. ; Chantrill, Lorraine A. ; Mawson, Amanda ; Samra, Jaswinder S. ; Kench, James G. ; Lovell, Jessica A. ; Daly, Roger J. ; Merrett, Neil D. ; Toon, Christopher ; Epari, Krishna ; Nguyen, Nam Q. ; Barbour, Andrew ; Zeps, Nikolajs ; Kakkar, Nipun ; Zhao, Fengmei ; Qing Wu, Yuan ; Wang, Min ; Muzny, Donna M. ; Fisher, William E. ; Charles Brunicardi, F. ; Hodges, Sally E. ; Reid, Jeffrey G. ; Drummond, Jennifer ; Chang, Kyle ; Han, Yi ; Lewis, Lora R. ; Dinh, Huyen ; Buhay, Christian J. ; Beck, Timothy ; Timms, Lee ; Sam, Michelle ; Begley, Kimberly ; Brown, Andrew ; Pai, Deepa ; Panchal, Ami ; Buchner, Nicholas ; De Borja, Richard ; Denroche, Robert E. ; Yung, Christina K. ; Serra, Stefano ; Onetto, Nicole ; Mukhopadhyay, Debabrata ; Tsao, Ming-Sound ; Shaw, Patricia A. ; Petersen, Gloria M. ; Gallinger, steven ; Hruban, Ralph H. ; Maitra, Anirban ; Iacobuzio-Donahue, Christine A. ; Schulick, Richard D. ; Wolfgang, Christopher L. ; Morgan, Richard A. ; Lawlor, Rita T. ; Capelli, Paola ; Corbo, Vincenzo ; Scardoni, Maria ; Tortora, Giampaolo ; Tempero, Margaret A. ; Mann, Karen M. ; Jenkins, Nancy A. ; Perez-Mancera, Pedro A. ; Adams, David J. ; Largaespada, David A. ; Wessels, Lodewyk F. A. ; Rust, Alistair G. ; Stein, Lincoln D. ; Tuveson, David A. ; Copeland, Neal G. ; Musgrove, Elizabeth A. ; Scarpa, Aldo ; Eshleman, James R. ; Hudson, Thomas J. ; Sutherland, Robert L. ; Wheeler, David A. ; Pearson, John V. ; McPherson, John D. ; Gibbs, Richard A. ; Grimmond, Sean M.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known [...]

Menée sur 53 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer séreux de l'endomètre, cette étude identifie de fréquentes mutations de gènes impliqués dans le remodelage de la chromatine ou de gènes d'un complexe ubiquitine ligase

Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes

Gallo, Matthieu Le ; O'Hara, Andrea J. ; Rudd, Meghan L. ; Urick, Mary Ellen ; Hansen, Nancy F. ; O'Neil, Nigel J. ; Price, Jessica C. ; Zhang, Suiyuan ; England, Bryant M. ; Godwin, Andrew K. ; Sgroi, Dennis C. ; Hieter, Philip ; Mullikin, James C. ; Merino, Maria J. ; Bell, Daphne W.

Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology. We used whole-exome sequencing to comprehensively search for somatic mutations within ~22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched [...]

Menée sur 414 échantillons de tumeurs primitives et 61 échantillons de lésions métastatiques prélevés sur des patientes atteintes d'un carcinome de l'endomètre, cette étude évalue l'association entre l'amplification, la surexpression ou une mutation du gène KRAS et l'agressivité des tumeurs

KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer

Birkeland, E. ; Wik, E. ; Mjos, S. ; Hoivik, E. A. ; Trovik, J. ; Werner, H. M. J. ; Kusonmano, K. ; Petersen, K. ; Raeder, M. B. ; Holst, F. ; Oyan, A. M. ; Kalland, K. H. ; Akslen, L. A. ; Simon, R. ; Krakstad, C. ; Salvesen, H. B.

Background: Three quarter of endometrial carcinomas are treated at early stage. Still, 15 to 20% of these patients experience recurrence, with little effect from systemic therapies. Homo sapiens v-Ki-ras2 Kirsten rat sarcoma viral oncogenes homologue (KRAS) mutations have been reported to have an important role in tumorigenesis for human cancers, but there is limited knowledge regarding clinical relevance of KRAS status in endometrial carcinomas. Methods: We have performed a comprehensive and [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel une E3-ligase, MKRN1, régule la sénescence cellulaire et la tumorigenèse d'un cancer gastrique

Acceleration of Gastric Tumorigenesis Through MKRN1-Mediated Posttranslational Regulation of p14ARF

Ko, Aram ; Shin, Ji-Young ; Seo, Jinho ; Lee, Kang-Duck ; Lee, Eun-Woo ; Lee, Min-Sik ; Lee, Han-Woong ; Choi, Il-Ju ; Jeong, Jin Sook ; Chun, Kyung-Hee ; Song, Jaewhan

Background We investigated whether Makorin ring finger protein 1 (MKRN1), an E3 ligase, affects p14ARF-associated cellular senescence and tumorigenesis by posttranslational modification in gastric tumorigenesis. Methods A link between MKRN1 and ARF was examined in MKRN1 null mouse embryonic fibroblasts (MEFs) and in human fibroblasts and gastric cancer cells by silencing MKRN1 using small interfering RNA (siRNA) and short hairpin RNA (shRNA). Ubiquitination and proteasomal degradation assays [...]

Cet article passe en revue les travaux récents sur le rôle joué par la voie de signalisation du facteur de transcription STAT3 dans les différentes étapes de l'évolution d'un carcinome hépatocellulaire

Potential Role of Signal Transducer and Activator of Transcription (STAT)3 Signaling Pathway in Inflammation, Survival, Proliferation and Invasion of Hepatocellular Carcinoma

Subramaniam, Aruljothi ; Shanmugam, Muthu K. ; Perumal, Ekambaram ; Li, Feng ; Nachiyappan, Alamelu ; Dai, Xiaoyun ; Swamy, Shivananju Nanjunda ; Ahn, Kwang Seok ; Kumar, Alan P. ; Tan, Benny K. H. ; Hui, Kam Man ; Sethi, Gautam

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but [...]

Menée sur des lignées cellulaires, cette étude met en évidence les rôles différents joués par les isoformes oncogéniques et non mutées du gène Ras dans la régulation de la voie de signalisation MAPK

Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling

Young, Amy ; Lou, David ; McCormick, Frank

H-Ras, K-Ras and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and non-redundant roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, while wild-type Ras mediates [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine kinase Akt régule, via la phosphorylation de la protéine Beclin 1, l'autophagie et la tumorigenèse

Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation

Wang, Richard C. ; Wei, Yongjie ; An, Zhenyi ; Zou, Zhongju ; Xiao, Guanghua ; Bhagat, Govind ; White, Michael ; Reichelt, Julia ; Levine, Beth

Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)–Akt axis is frequent in human cancer. Here, e show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin [...]

Cet article passe en revue les travaux récents sur le rôle du catabolisme d'un acide aminé, le tryptophane, dans la régulation des réponses immunitaires antitumorales

Tryptophan Catabolism in Cancer: Beyond IDO and Tryptophan Depletion

Platten, Michael ; Wick, Wolfgang ; Van den Eynde, Benoît J.

Tryptophan catabolism in cancer is increasingly being recognized as an important microenvironmental factor that suppresses antitumor immune responses. It has been proposed that the essential amino acid tryptophan is catabolized in the tumor tissue by the rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO) expressed in tumor cells or antigen-presenting cells. This metabolic pathway creates an immunosuppressive milieu in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and [...]

Menée à l'aide d'un modèle murin de cancer colorectal, cette étude montre que la voie de signalisation Nanog favorise l'évolution des cellules souches cancéreuses et leur échappement au système immunitaire

Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Noh, Kyung Hee ; Kim, Bo Wook ; Song, Kwon-Ho ; Cho, Hanbyoul ; Lee, Young-Ho ; Kim, Jin Hee ; Chung, Joon-Yong ; Kim, Jae-Hoon ; Hewitt, Stephen M. ; Seong, Seung-Yong ; Mao, Chih-Ping ; Wu, T. C. ; Kim, Tae Woo

Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell–like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a [...]

Menée à l'aide de modèles murins de cancer cutané, cette étude montre que, selon le tissu où s'exprime une protéine de l'inflammasome, ASC, celle-ci peut favoriser la croissance tumorale ou jouer un rôle de suppresseur de tumeurs

Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis

Drexler, Stefan K. ; Bonsignore, Luca ; Masin, Mark ; Tardivel, Aubry ; Jackstadt, Rene ; Hermeking, Heiko ; Schneider, Pascal ; Gross, Olaf ; Tschopp, Jurg ; Yazdi, Amir S.

A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor- or caspase-1–deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully [...]

Menée in vitro, cette étude met en évidence le rôle joué par un facteur de transcription associé aux cellules souches embryonnaires, TCF3, dans la régulation de la croissance d'une tumeur du sein

Control of Breast Cancer Growth and Initiation by the Stem Cell–Associated Transcription Factor TCF3

Slyper, Michal ; Shahar, Amit ; Bar-Ziv, Anat ; Granit, Roy Z. ; Hamburger, Tamar ; Maly, Bella ; Peretz, Tamar ; Ben-Porath, Ittai

Regulatory factors controlling stem cell identity and self-renewal are often active in aggressive cancers and are thought to promote their growth and progression. TCF3 (also known as TCF7L1) is a member of the TCF/LEF transcription factor family that is central in regulating epidermal and embryonic stem cell identity. We found that TCF3 is highly expressed in poorly differentiated human breast cancers, preferentially of the basal-like subtype. This suggested that TCF3 is involved in the [...]

Menée sur 5 échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence une importante hétérogénéité moléculaire des tumeurs chez un même patient et d'un patient à l'autre

Single molecule genomic data delineate patient-specific tumor profiles and cancer stem cell organization

Sottoriva, Andrea ; Spiteri, Inmaculada ; Shibata, Darryl ; Curtis, Christina ; Tavare, Simon

Substantial evidence supports the concept that cancers are organized in a cellular hierarchy with cancer stem cells (CSCs) at the apex. To date, the primary evidence for CSCs derives from transplantation assays, which have known limitations. In particular, they are unable to report on the fate of cells within the original human tumor. Due to the difficulty in measuring tumor characteristics in patients, cellular organization and other aspects of cancer dynamics have not been quantified [...]

Cet article plaide pour la mise en place d'un inventaire exhaustif des circuits de rétroaction entre voies de signalisation à l'œuvre au sein des cellules cancéreuses

A Missing Link in Genotype-Directed Cancer Therapy

Bernards, Rene

Genotype-directed therapy holds great promise for the treatment of cancer, but crosstalk between signaling pathways often confounds simple genotype-drug response relationships. To deliver on the promise of precision medicine, a coordinated effort is needed to make a comprehensive inventory of the many signaling feedback circuits that exist in cancer cells.