Menée sur des échantillons tumoraux prélevés sur 15 patients atteints d'un adénocarcinome gastrique, cette étude de séquençage des exons met en évidence des mutations somatiques de gènes impliqués dans le remodelage de la chromatine et l'adhérence cellulaire

Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

Zang, Zhi Jiang ; Cutcutache, Ioana ; Poon, Song Ling ; Zhang, Shen Li ; McPherson, John R. ; Tao, Jiong ; Rajasegaran, Vikneswari ; Heng, Hong Lee ; Deng, Niantao ; Gan, Anna ; Lim, Kiat Hon ; Ong, Choon Kiat ; Huang, DaChuan ; Chin, Sze Yung ; Tan, Iain Beehuat ; Ng, Cedric Chuan Young ; Yu, Willie ; Wu, Yingting ; Lee, Minghui ; Wu, Jeanie ; Poh, Dianne ; Wan, Wei Keat ; Rha, Sun Young ; So, Jimmy ; Salto-Tellez, Manuel ; Yeoh, Khay Guan ; Wong, Wai Keong ; Zhu, Yi-Jun ; Futreal, P. Andrew ; Pang, Brendan ; Ruan, Yijun ; Hillmer, Axel M. ; Bertrand, Denis ; Nagarajan, Niranjan ; Rozen, Steve ; Teh, Bin Tean ; Tan, Patrick

Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of [...]

Menée sur des échantillons prélevés sur 29 patientes atteintes d'un carcinome canalaire in situ (CCIS), 26 patientes atteintes d'un carcinome canalaire invasif (CCI) et 23 patientes atteintes de CCIS et CCI synchrones, cette étude analyse la fréquence des mutations de la région D310 de l'ADN mitochondrial

Mitochondrial D310 mutations in the early development of breast cancer

Xu, C. ; Tran-Thanh, D. ; Ma, C. ; May, K. ; Jung, J. ; Vecchiarelli, J. ; Done, S. J.

Background: The role of mitochondrial DNA (mtDNA) mutations in the development of breast cancer is largely unknown. In this study, we investigated the frequency and pattern of mutations in the D310 region, the most commonly mutated region in mtDNA, in a series of breast lesions. Methods: Using capillary electrophoresis, we genotyped the D310 sequence of neoplastic epithelial cells from 23 patients with synchronous ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), 26 patients [...]

Menée sur 104 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer primitif du sein triplement négatif, cette étude met en évidence un large spectre d'évolution génomique dans ces tumeurs

The clonal and mutational evolution spectrum of primary triple-negative breast cancers

Shah, Sohrab P. ; Roth, Andrew ; Goya, Rodrigo ; Oloumi, Arusha ; Ha, Gavin ; Zhao, Yongjun ; Turashvili, Gulisa ; Ding, Jiarui ; Tse, Kane ; Haffari, Gholamreza ; Bashashati, Ali ; Prentice, Leah M. ; Khattra, Jaswinder ; Burleigh, Angela ; Yap, Damian ; Bernard, Virginie ; McPherson, Andrew ; Shumansky, Karey ; Crisan, Anamaria ; Giuliany, Ryan ; Heravi-Moussavi, Alireza ; Rosner, Jamie ; Lai, Daniel ; Birol, Inanc ; Varhol, Richard ; Tam, Angela ; Dhalla, Noreen ; Zeng, Thomas ; Ma, Kevin ; Chan, Simon K. ; Griffith, Malachi ; Moradian, Annie ; Cheng, S. W. Grace ; Morin, Gregg B. ; Watson, Peter ; Gelmon, Karen ; Chia, Stephen ; Chin, Suet-Feung ; Curtis, Christina ; Rueda, Oscar M. ; Pharoah, Paul D. ; Damaraju, Sambasivarao ; Mackey, John ; Hoon, Kelly ; Harkins, Timothy ; Tadigotla, Vasisht ; Sigaroudinia, Mahvash ; Gascard, Philippe ; Tlsty, Thea ; Costello, Joseph F. ; Meyer, Irmtraud M. ; Eaves, Connie J. ; Wasserman, Wyeth W. ; Jones, Steven ; Huntsman, David ; Hirst, Martin ; Caldas, Carlos ; Marra, Marco A. ; Aparicio, Samuel

Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput [...]

Cet article passe en revue les travaux récents sur le rôle des micro-ARNs dans la biologie des cancers

microRNA involvement in human cancer

Iorio, Marilena V. ; Croce, Carlo M.

When, approximately 20 years ago, investigators first determined that components of the genome considered nonfunctional had, in fact, gene regulatory capacity, they probably had no idea of their potential in controlling cell fate, and were forced to revise and somehow reorganize their view of the molecular biology.Indeed, it is currently well documented how a class of small non coding RNAs, microRNAs, are conserved among the species, expressed in different tissues and cell types, and involved [...]

Menée in vitro et in vivo, cette étude montre que l'activité des facteurs de transcription de la famille Gli est nécessaire au développement d'une tumeur du pancréas lié à l'activation du gène Kras

The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis

Rajurkar, Mihir ; De Jesus-Monge, Wilfredo E. ; Driscoll, David R. ; Appleman, Victoria A. ; Huang, He ; Cotton, Jennifer L. ; Klimstra, David S. ; Zhu, Lihua J. ; Simin, Karl ; Xu, Lan ; McMahon, Andrew P. ; Lewis, Brian C. ; Mao, Junhao

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, is thought to be initiated by KRAS activation. Here we find that transcriptional activation mediated by the Gli family of transcription factors, although dispensable for pancreatic development, is required for Kras-induced proliferation and survival in primary pancreatic epithelial cells in culture and for Kras-driven pancreatic intraepithelial neoplasia and PDAC formation in vivo. Further, ectopic Gli1 [...]

Menée sur des lignées cellulaires de cancer du pancréas, cette étude met en évidence un mécanisme par lequel la chimiokine CXCL12 active la co-expression des récepteurs CXCR4 et CXCR7

Chemokine CXCL12 activates dual CXCR4 and CXCR7-mediated signaling pathways in pancreatic cancer cells

Heinrich, Eileen ; Lee, Wendy ; Lu, Jianming ; Lowy, Andrew ; Kim, Joseph

BACKGROUND:Previously assumed to be a select ligand for chemokine receptor CXCR4, chemokine CXCL12 is now known to activate both CXCR4 and CXCR7. However, very little is known about the co-expression of these receptors in cancer cells.METHODS:We used immunohistochemistry to determine the extent of co-expression in pancreatic cancer tissue samples and immunoblotting to verify expression in pancreatic cancer cell lines. In cell culture studies, siRNA was used to knock down expression of CXCR4, [...]

Menée sur un modèle murin, cette étude met en évidence un mécanisme de régulation d'une tumorigenèse de la prostate impliquant un gène suppresseur de tumeurs, Nkx3.1, et un oncogène, Myc

Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis

Anderson, Philip D. ; McKissic, Sydika A. ; Logan, Monica ; Roh, Meejeon ; Franco, Omar E. ; Wang, Jie ; Doubinskaia, Irina ; Meer, Riet van der ; Hayward, Simon W. ; Eischen, Christine M. ; Eltoum, Isam-Eldin ; Abdulkadir, Sarki A.

Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets [...]

Cet article passe en revue les travaux récents mettant en évidence le rôle de la réponse immunitaire face aux cellules sénescentes dans la progression d'un cancer

Immune surveillance of senescent cells - biological significance in cancer- and non-cancer pathologies

Hoenicke, Lisa ; Zender, Lars

Cellular senescence, a state of stable growth arrest, can occur in response to various stress stimuli such as telomere shortening, treatment with chemotherapeutic drugs or the aberrant activation of oncogenes. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it has become clear that this ‘secretory phenotype’ can have pro- as well as anti-tumorigenic effects. Recent work from our laboratory showed that premalignant, senescent hepatocytes [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel le facteur de transcription SIX1 favorise la dissémination lymphatique des cellules de cancer du sein

SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer

Wang, Chu-An ; Jedlicka, Paul ; Patrick, Aaron N. ; Micalizzi, Douglas S. ; Lemmer, Kimberly C. ; Deitsch, Erin ; Casás-Selves, Matias ; Harrell, J. Chuck ; Ford, Heide L.

An association between lymph node metastasis and poor prognosis in breast cancer was observed decades ago. However, the mechanisms by which tumor cells infiltrate the lymphatic system are not completely understood. Recently, it has been proposed that the lymphatic system has an active role in metastatic dissemination and that tumor-secreted growth factors stimulate lymphangiogenesis. We therefore investigated whether SIX1, a homeodomain-containing transcription factor previously associated in [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme de régulation des cellules souches de cancer du sein par la chimiokine CCL2

CCL2 mediates crosstalk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells

Tsuyada, Akihiro ; Chow, Amy ; Wu, Jun ; Somlo, George ; Chu, Peiguo ; Loera, Sofia ; Luu, Thehang ; Li, Xuejun ; Wu, Xiwei ; Ye, Wei ; Chen, Shiuan ; Zhou, Weiying ; Yu, Yang ; Wang, Yuan-Zhong ; Ren, Xiubao ; Li, Hui ; Scherle, Peggy ; Kuroki, Yukio ; Wang, Shizhen Emily

Cancer stem cells (CSCs) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer (BC) stem cells. We found that compared to normal fibroblasts, primary cancer-associated fibroblasts (CAFs) and fibroblasts [...]

Cet article passe en revue les méthodes permettant de mener des études sur des voies de signalisation fonctionnelles à partir de données génomiques

Pathway analysis of genomic data: concepts, methods and prospects for future development

Ramanan, Vijay K. ; Shen, Li ; Moore, Jason H. ; Saykin, Andrew J.

Genome-wide data sets are increasingly being used to identify biological pathways and networks underlying complex diseases. In particular, analyzing genomic data through sets defined by functional pathways offers the potential of greater power for discovery and natural connections to biological mechanisms. With the burgeoning availability of next-generation sequencing, this is an opportune moment to revisit strategies for pathway-based analysis of genomic data. Here, we synthesize relevant [...]

A l'aide d'un modèle statistique, cette étude montre qu'il est relativement aisé d'identifier une personne à partir de données issues d'études d'association sur le génome entier

On Sharing Quantitative Trait GWAS Results in an Era of Multiple-omics Data and the Limits of Genomic Privacy

Im, Hae Kyung ; Gamazon, Eric R ; Nicolae, Dan L ; Cox, Nancy J

Recent advances in genome-scale, system-level measurements of quantitative phenotypes (transcriptome, metabolome, and proteome) promise to yield unprecedented biological insights. In this environment, broad dissemination of results from genome-wide association studies (GWASs) or deep-sequencing efforts is highly desirable. However, summary results from case-control studies (allele frequencies) have been withdrawn from public access because it has been shown that they can be used for inferring [...]