Menée à partir d'échantillons de tissu tumoral et de tissu sain prélevés sur 100 patients atteints d'un cancer de l'estomac, cette étude identifie de nouveaux gènes dont les mutations sont associées au développement de la maladie

Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer

Wang, Kai ; Yuen, Siu Tsan ; Xu, Jiangchun ; Lee, Siu Po ; Yan, Helen H. N. ; Shi, Stephanie T. ; Siu, Hoi Cheong ; Deng, Shibing ; Chu, Kent Man ; Law, Simon ; Chan, Kok Hoe ; Chan, Annie S. Y. ; Tsui, Wai Yin ; Ho, Siu Lun ; Chan, Anthony K. W. ; Man, Jonathan L. K. ; Foglizzo, Valentina ; Ng, Man Kin ; Chan, April S. ; Ching, Yick Pang ; Cheng, Grace H. W. ; Xie, Tao ; Fernandez, Julio ; Li, Vivian S. W. ; Clevers, Hans ; Rejto, Paul A. ; Mao, Mao ; Leung, Suet Yi

Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. [...]

Menée initialement sur des échantillons tumoraux prélevés sur 30 patients atteints d'un carcinome gastrique diffus, puis sur une cohorte complémentaire de 57 patients, cette étude japonaise identifie la présence fréquente de mutations du gène RHOA

Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma

Kakiuchi, Miwako ; Nishizawa, Takashi ; Ueda, Hiroki ; Gotoh, Kengo ; Tanaka, Atsushi ; Hayashi, Akimasa ; Yamamoto, Shogo ; Tatsuno, Kenji ; Katoh, Hiroto ; Watanabe, Yoshiaki ; Ichimura, Takashi ; Ushiku, Tetsuo ; Funahashi, Shinichi ; Tateishi, Keisuke ; Wada, Ikuo ; Shimizu, Nobuyuki ; Nomura, Sachiyo ; Koike, Kazuhiko ; Seto, Yasuyuki ; Fukayama, Masashi ; Aburatani, Hiroyuki ; Ishikawa, Shumpei

Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction. We performed whole-exome sequencing on 30 DGC cases and found recurrent RHOA nonsynonymous mutations. With validation sequencing of an additional 57 cases, RHOA mutation was observed in 25.3% (22/87) of DGCs, with mutational hotspots affecting the Tyr42, Arg5 and Gly17 residues in RHOA protein. These positions are highly conserved among RHO family members, and [...]

Menée à partir d'échantillons tumoraux prélevés sur 70 patients américains atteints d'une tumeur à cellules germinales ayant été traitée par une chimiothérapie à base de cisplatine, puis sur neuf lignées cellulaires, cette étude identifie la présence de mutations dans plusieurs gènes (PIK3CA, AKT, RAS, et FGFR3 mais pas BRAF) en association avec la résistance thérapeutique

Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Feldman, Darren R. ; Iyer, Gopa ; Van Alstine, Lindsay ; Patil, Sujata ; Al-Ahmadie, Hikmat A. ; Reuter, Victor E. ; Bosl, George J. ; Chaganti, Raju S K. ; Solit, David B.

Purpose: A previous study noted frequent B-RAF mutations among European patients with cisplatin-resistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among GCT patients at our center. Patients and Methods: Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and [...]

Menée à partir d'échantillons prélevés sur 50 patients atteints d'une leucémie prolymphocytaire T, cette étude identifie un ensemble de gènes dont les mutations sont associées au développement de la maladie

Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia

Kiel, Mark J. ; Velusamy, Thirunavukkarasu ; Rolland, Delphine ; Sahasrabuddhe, Anagh A. ; Chung, Fuzon ; Bailey, Nathanael G. ; Schrader, Alexandra ; Li, Bo ; Li, Jun Z. ; Ozel, Ayse B. ; Betz, Bryan L. ; Miranda, Roberto N. ; Medeiros, L. Jeffrey ; Zhao, Lili ; Herling, Marco ; Lim, Megan S. ; Elenitoba-Johnson, Kojo S. J.

The comprehensive genetic alterations underlying the pathogenesis of T-Prolymphocytic Leukemia (T-PLL) are unknown. To address this, we performed whole genome sequencing (WGS), whole exome sequencing (WES), high-resolution copy number analysis and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10 and CHEK2. Strikingly, WGS and/or WES showed largely mutually-exclusive [...]

Menée à partir de 1 420 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein et incluses dans la cohorte METABRIC, cette étude identifie diverses mutations du gène TP53 en association avec divers sous-types moléculaires de la maladie

TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance

Silwal-Pandit, Laxmi ; Moen Vollan, Hans Kristian ; Chin, Suet-Feung ; Rueda, Oscar M. ; McKinney, Steven E ; Osako, Tomo ; Quigley, David ; Kristensen, Vessela N. ; Aparicio, Samuel ; Borresen-Dale, Anne-Lise ; Caldas, Carlos ; Langerod, Anita

Purpose: In breast cancer, the TP53 gene is frequently mutated and the mutations have been associated with poor prognosis. The prognostic impact of the different types of TP53 mutations across the different molecular subtypes is still poorly understood. Here, we characterize the spectrum and prognostic significance of TP53 mutations with respect to the PAM50 subtypes and Integrative Clusters (IC). Experimental design: TP53 mutation status was obtained for 1420 tumor samples from the METABRIC [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en aval de la voie de signalisation de l'oncogène KRAS muté, la protéine Yap favorise la progression d'un adénocarcinome canalaire du pancréas

Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma

Zhang, Weiying ; Nandakumar, Nivedita ; Shi, Yuhao ; Manzano, Mark ; Smith, Alias ; Graham, Garrett ; Gupta, Swati ; Vietsch, Eveline E. ; Laughlin, Sean Z. ; Wadhwa, Mandheer ; Chetram, Mahandranauth ; Joshi, Mrinmayi ; Wang, Fen ; Kallakury, Bhaskar ; Toretsky, Jeffrey ; Wellstein, Anton ; Yi, Chunling

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates and frequently carries oncogenic KRAS mutation. However, KRAS has thus far not been a viable therapeutic target. We found that the abundance of YAP mRNA, which encodes Yes-associated protein (YAP), a protein regulated by the Hippo pathway during tissue development and homeostasis, was increased in human PDAC tissue compared with that in normal pancreatic epithelia. In genetically engineered KrasG12D and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via le microenvironnement tumoral, la galectine 1 favorise le développement d'un adénocarcinome canalaire du pancréas

Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation

Martinez-Bosch, Neus ; Fernandez-Barrena, Maite G ; Moreno, Mireia ; Ortiz-Zapater, Elena ; Munne-Collado, Jessica ; Iglesias, Mar ; Andre, Sabine ; Gabius, Hans-Joachim ; Hwang, Rosa F. ; Poirier, Francoise ; Navas, Carolina ; Guerra, Carmen ; Fernandez-Zapico, Martin E ; Navarro, Pilar

Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutuic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de la protéine pro-apoptique Bim, certaines mutations d'oncogènes et de gènes suppresseurs de tumeurs favorisent le développement d'un adénome de l'intestin

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β

Wiener, Zoltan ; Band, Arja M. ; Kallio, Pauliina ; Högström, Jenny ; Hyvönen, Ville ; Kaijalainen, Seppo ; Ritvos, Olli ; Haglund, Caj ; Kruuna, Olli ; Robine, Sylvie ; Louvard, Daniel ; Ben-Neriah, Yinon ; Alitalo, Kari

In the majority of microsatellite-stable colorectal cancers (CRCs), an initiating mutation occurs in the adenomatous polyposis coli (APC) or β-catenin gene, activating the β-catenin/TCF pathway. The progression of resulting adenomas is associated with oncogenic activation of KRas and inactivation of the p53 and TGF-β/Smad functions. Most established CRC cell lines contain mutations in the TGF-β/Smad pathway, but little is known about the function of TGF-β in the early phases of intestinal [...]

Cet article passe en revue les travaux récents sur le rôle joué par les interactions entre la flore microbienne intestinale et le système immunitaire dans la cancérogenèse

The Fire Within: Microbes Inflame Tumors

Gagliani, Nicola ; Hu, Bo ; Huber, Samuel ; Elinav, Eran ; Flavell, Richard A

The immune system and the microbiota mutually interact to maintain homeostasis in the intestine. However, components of the microbiota can alter this balance and promote chronic inflammation, promoting intestinal tumor development. We review recent advances in understanding the complex interactions between the microbiota and the innate and adaptive immune systems and discuss their potential to lead us in new directions for understanding cancer biology and treatment.

Menée notamment sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de gènes impliqués dans la polyadénylation alternative, la protéine CFIm25 exerce une fonction de suppresseur de tumeurs dans un glioblastome

CFIm25 links alternative polyadenylation to glioblastoma tumour suppression

Masamha, Chioniso P. ; Xia, Zheng ; Yang, Jingxuan ; Albrecht, Todd R. ; Li, Min ; Shyu, Ann-Bin ; Li, Wei ; Wagner, Eric J.

The global shortening of messenger RNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression. The 3′ untranslated region (UTR) truncation of growth-promoting mRNA transcripts that relieves intrinsic microRNA- and AU-rich-element-mediated repression has been observed to correlate with cellular transformation; however, the importance to tumorigenicity of RNA [...]

Menée à l'aide d'un modèle murin, cette étude montre que l'origine des monocytes tumoraux, qui favorisent la progression tumorale, réside majoritairement dans la moelle osseuse et non dans la rate

Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes

Shand, Francis H. W. ; Ueha, Satoshi ; Otsuji, Mikiya ; Koid, Suang Suang ; Shichino, Shigeyuki ; Tsukui, Tatsuya ; Kosugi-Kanaya, Mizuha ; Abe, Jun ; Tomura, Michio ; Ziogas, James ; Matsushima, Kouji

Myeloid cells such as monocytes and monocyte-derived macrophages promote tumor progression. Recent reports suggest that extramedullary hematopoiesis sustains a sizable reservoir of tumor-infiltrating monocytes in the spleen. However, the influence of the spleen on tumor development and the extent to which spleen monocytes populate the tumor relative to bone marrow (BM) monocytes remain controversial. Here, we used mice expressing the photoconvertible protein Kikume Green-Red to track the [...]

A partir de données portant sur 5 887 patients d'origine européenne et atteints d'un cancer de la prostate, cette étude identifie des polymorphismes à simple nucléotide de gènes de la voie de signalisation du facteur de croissance analogue à l'insuline, notamment IGF2-AS et SSTR2, impliqués dans la progression de la maladie

Insulin-like Growth Factor Pathway Genetic Polymorphisms, Circulating IGF1 and IGFBP3, and Prostate Cancer Survival

Cao, Yin ; Lindström, Sara ; Schumacher, Fredrick ; Stevens, Victoria L. ; Albanes, Demetrius ; Berndt, Sonja I. ; Boeing, Heiner ; Bas Bueno-de-Mesquita, H. ; Canzian, Federico ; Chamosa, Saioa ; Chanock, Stephen J. ; Diver, W. Ryan ; Gapstur, Susan M. ; Gaziano, J. Michael ; Giovannucci, Edward L. ; Haiman, Christopher A. ; Henderson, Brian ; Johansson, Mattias ; Marchand, Loïc Le ; Palli, Domenico ; Rosner, Bernard ; Siddiq, Afshan ; Stampfer, Meir ; Stram, Daniel O. ; Tamimi, Rulla ; Travis, Ruth C. ; Trichopoulos, Dimitrios ; Willett, Walter C. ; Yeager, Meredith ; Kraft, Peter ; Hsing, Ann W. ; Pollak, Michael ; Lin, Xihong ; Ma, Jing

Background : The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown. Methods : Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une boucle de rétroaction positive entre des cellules de cancer du sein surexprimant GM-CSF et des macrophages surexprimant CCL18 favorise le processus métastatique

A Positive Feedback Loop between Mesenchymal-like Cancer Cells and Macrophages Is Essential to Breast Cancer Metastasis

Su, Shicheng ; Liu, Qiang ; Chen, Jingqi ; Chen, Jianing ; Chen, Fei ; He, Chonghua ; Huang, Di ; Wu, Wei ; Lin, Ling ; Huang, Wei ; Zhang, Jin ; Cui, Xiuying ; Zheng, Fang ; Li, Haiyan ; Yao, Herui ; Su, Fengxi ; Song, Erwei

The close vicinity of cancer cells undergoing epithelial-mesenchymal transition (EMT) and tumor-associated macrophages (TAMs) at the invasive front of tumors suggests that these two cell type may mutually interact. We show that mesenchymal-like breast cancer cells activate macrophages to a TAM-like phenotype by GM-CSF. Reciprocally, CCL18 from TAMs induces cancer cell EMT, forming a positive feedback loop, in coculture systems and humanized mice. Inhibition of GM-CSF or CCL18 breaks this loop [...]

A partir d'une revue de la littérature, cette étude met en garde contre l'usage d'un solvant, le diméthylsulfoxyde, dans les études mettant en œuvre des médicaments à base de sels de platine

Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin and Other Platinum Complexes

Hall, Matthew D ; Telma, Katherine A. ; Chang, Ki-Eun ; Lee, Tobie D. ; Madigan, James P. ; Lloyd, John R. ; Goldlust, Ian S. ; Hoeschele, James D. ; Gottesman, Michael M.

The platinum drugs cisplatin, carboplatin and oxaliplatin are highly utilized in the clinic and as a consequence are extensively studied in the laboratory setting. In this study, we examined the literature and found a significant number of studies (11 - 34%) in prominent cancer journals utilizing cisplatin dissolved in dimethylsulfoxide (DMSO). However, dissolving cisplatin in DMSO for laboratory-based studies results in ligand displacement and changes to the structure of the complex. We [...]

Cet article passe en revue les travaux récents sur le rôle joué par des dysfonctionnements du réticulum endoplasmique dans la cancérogenèse

Endoplasmic Reticulum Stress in Malignancy

Clarke, Hanna J ; Chambers, Joseph E ; Liniker, Elizabeth ; Marciniak, Stefan J

The combination of relative nutrient deprivation and dysregulation of protein synthesis make malignant cells especially prone to protein misfolding. Endoplasmic reticulum stress, which results from protein misfolding within the secretory pathway, has a profound effect on cancer cell proliferation and survival. In this review, we examine the evidence implicating endoplasmic reticulum dysfunction in the pathology of cancer and discuss how recent findings may help to identify novel therapeutic [...]

Menée à l'aide d'un modèle murin, cette étude montre que la croissance d'une tumeur mammaire induit l'accumulation de macrophages associés aux tumeurs qui, d'un point de vue phénotypique et fonctionnel, diffèrent des macrophages présents dans les tissus mammaires

The Cellular and Molecular Origin of Tumor-Associated Macrophages

Franklin, Ruth A. ; Liao, Will ; Sarkar, Abira ; Kim, Myoungjoo V. ; Bivona, Michael R. ; Liu, Kang ; Pamer, Eric G. ; Li, Ming O.

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases including cancer. Here, we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation [...]