A partir d'échantillons de tumeurs primitives et de métastases prélevés sur 68 patients atteints d'un adénocarcinome canalaire du pancréas, cette étude identifie un ensemble d'anomalies génomiques

Clinical study of genomic drivers in pancreatic ductal adenocarcinoma

Barrett, Michael T. ; Deiotte, Ray ; Lenkiewicz, Elizabeth ; Malasi, Smriti ; Holley, Tara ; Evers, Lisa ; Posner, Richard G. ; Jones, Timothy ; Han, Haiyong ; Sausen, Mark ; Velculescu, Victor E. ; Drebin, Jeffrey ; O'Dwyer, Peter ; Jameson, Gayle ; Ramanathan, Ramesh K. ; Von Hoff, Daniel D.

Background: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. Methods: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled [...]

A partir de 99 échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude analyse les anomalies du nombre de copies de gènes et leurs effets sur l'expression des gènes impliqués dans des voies de signalisation associées à la cancérogenèse

Comprehensive analysis of copy number aberrations in microsatellite stable colon cancer in view of stromal component

Alonso, M. Henar ; Aussó, Susanna ; López-Doriga, Adriana ; Cordero, David ; Guinó, Elisabet ; Solé, Xavier ; Barenys, Merce ; de Oca, Javier ; Capella, Gabriel ; Salazar, Ramon ; Sanz-Pamplona, Rebeca ; Moreno, Víctor

Background: Somatic copy number aberrations (CNAs) are common acquired changes in cancer cells having an important role in the progression of colon cancer (colorectal cancer, CRC). This study aimed to perform a characterisation of CNA and their impact in gene expression. Methods: Copy number aberrations were inferred from SNP array data in a series of 99 CRC. Copy number aberration events were calculated and used to assess the association between copy number dosage, clinical and molecular [...]

A partir de données issues du projet "The Cancer Genome Atlas", puis menée sur 2 cohortes indépendantes de 43 et 40 patientes atteintes d'un carcinome invasif du sein, cette étude identifie des événements d'épissage alternatif de 5 gènes en association avec 3 sous-types de cancer du sein (ER+ HER2-, ER- HER2- et HER2+)

Widespread alternative exon usage in clinically distinct subtypes of Invasive Ductal Carcinoma

Bjørklund, Sunniva Stordal ; Panda, Anshuman ; Kumar, Surendra ; Seiler, Michael ; Robinson, Doug ; Gheeya, Jinesh ; Yao, Ming ; Alnæs, Grethe I. Grenaker ; Toppmeyer, Deborah ; Riis, Margit ; Naume, Bjørn ; Børresen-Dale, Anne-Lise ; Kristensen, Vessela N. ; Ganesan, Shridar ; Bhanot, Gyan

Cancer cells can have different patterns of exon usage of individual genes when compared to normal tissue, suggesting that alternative splicing may play a role in shaping the tumor phenotype. The discovery and identification of gene variants has increased dramatically with the introduction of RNA-sequencing technology, which enables whole transcriptome analysis of known, as well as novel isoforms. Here we report alternative splicing and transcriptional events among subtypes of invasive ductal [...]

A partir de 491 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un médulloblastome, cette étude identifie notamment des anomalies génomiques en association avec 2 sous-types de la maladie

The whole-genome landscape of medulloblastoma subtypes

Northcott, Paul A. ; Buchhalter, Ivo ; Morrissy, A. Sorana ; Hovestadt, Volker ; Weischenfeldt, Joachim ; Ehrenberger, Tobias ; Grobner, Susanne ; Segura-Wang, Maia ; Zichner, Thomas ; Rudneva, Vasilisa A. ; Warnatz, Hans-Jörg ; Sidiropoulos, Nikos ; Phillips, Aaron H. ; Schumacher, Steven ; Kleinheinz, Kortine ; Waszak, Sebastian M. ; Erkek, Serap ; Jones, David T. W. ; Worst, Barbara C. ; Kool, Marcel ; Zapatka, Marc ; Jager, Natalie ; Chavez, Lukas ; Hutter, Barbara ; Bieg, Matthias ; Paramasivam, Nagarajan ; Heinold, Michael ; Gu, Zuguang ; Ishaque, Naveed ; Jäger-Schmidt, Christina ; Imbusch, Charles D. ; Jugold, Alke ; Hübschmann, Daniel ; Risch, Thomas ; Amstislavskiy, Vyacheslav ; Gonzalez, Francisco German Rodriguez ; Weber, Ursula D. ; Wolf, Stephan ; Robinson, Giles W. ; Zhou, Xin ; Wu, Gang ; Finkelstein, David ; Liu, Yanling ; Cavalli, Florence M. G. ; Luu, Betty ; Ramaswamy, Vijay ; Wu, Xiaochong ; Koster, Jan ; Ryzhova, Marina ; Cho, Yoon-Jae ; Pomeroy, Scott L. ; Herold-Mende, Christel ; Schuhmann, Martin ; Ebinger, Martin ; Liau, Linda M. ; Mora, Jaume ; McLendon, Roger E. ; Jabado, Nada ; Kumabe, Toshihiro ; Chuah, Eric ; Ma, Yussanne ; Moore, Richard A. ; Mungall, Andrew J. ; Mungall, Karen L. ; Thiessen, Nina ; Tse, Kane ; Wong, Tina ; Jones, Steven J. M. ; Witt, Olaf ; Milde, Till ; von Deimling, Andreas ; Capper, David ; Korshunov, Andrey ; Yaspo, Marie-Laure ; Kriwacki, Richard ; Gajjar, Amar ; Zhang, Jinghui ; Beroukhim, Rameen ; Fraenkel, Ernest ; Korbel, Jan O. ; Brors, Benedikt ; Schlesner, Matthias ; Eils, Roland ; Marra, Marco A. ; Pfister, Stefan M. ; Taylor, Michael D. ; Lichter, Peter

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en réponse à des brisures double-brin de l'ADN causées par des rayonnements ionisants ou un agent chimiothérapeutique, une histone méthyltransférase (G9a) favorise la recombinaison homologue et la survie des cellules cancéreuses

G9a coordinates with the RPA complex to promote DNA damage repair and cell survival

Yang, Qiaoyan ; Zhu, Qian ; Lu, Xiaopeng ; Du, Yipeng ; Cao, Linlin ; Shen, Changchun ; Hou, Tianyun ; Li, Meiting ; Li, Zhiming ; Liu, Chaohua ; Wu, Di ; Xu, Xingzhi ; Wang, Lina ; Wang, Haiying ; Zhao, Ying ; Yang, Yang ; Zhu, Wei-Guo

Histone methyltransferase G9a has critical roles in promoting cancer-cell growth and gene suppression, but whether it is also associated with the DNA damage response is rarely studied. Here, we report that loss of G9a impairs DNA damage repair and enhances the sensitivity of cancer cells to radiation and chemotherapeutics. In response to DNA double-strand breaks (DSBs), G9a is phosphorylated at serine 211 by casein kinase 2 (CK2) and recruited to chromatin. The chromatin-enriched G9a can then [...]

Menée in vitro et in vivo sur des modèles de carcinome rénal à cellules claires, cette étude met en évidence des mécanismes par lesquels les cellules cancéreuses n'exprimant pas le gène suppresseur de tumeurs pVHL dépendent, pour leur survie, de la méthyltransférase EZH1

HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase

Chakraborty, Abhishek A. ; Nakamura, Eijiro ; Qi, Jun ; Creech, Amanda ; Jaffe, Jacob D. ; Paulk, Joshiawa ; Novak, Jesse S. ; Nagulapalli, Kshithija ; McBrayer, Samuel K. ; Cowley, Glenn S. ; Pineda, Javier ; Song, Jiaxi ; Wang, Yaoyu E. ; Carr, Steven A. ; Root, David E. ; Signoretti, Sabina ; Bradner, James E. ; Kaelin, William G.

Clear cell renal cell carcinoma is the most common form of kidney cancer, and it is typically linked to the loss of von Hippel–Lindau protein (pVHL), a tumor suppressor. This loss results in activation of genes that are normally induced by hypoxia, including some histone demethylases. Chakraborty et al. discovered that increased H3K27 demethylase activity renders pVHL-deficient cells hyperdependent on an opposing H3K27 methyltransferase, EZH1, for survival. Inhibition of EZH1 is lethal for [...]

A partir d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer héréditaire du sein (11 familles), cette étude française suggère notamment que le gène ATM exerce une fonction de suppresseur de tumeurs

Combined tumor genomic profiling and exome sequencing in a breast cancer family implicates ATM in tumorigenesis: a proof of principle study

Bubien, Virginie ; Bonnet, Françoise ; Dupiot-Chiron, Jennifer ; Barouk-Simonet, Emmanuelle ; Jones, Natalie ; de Reyniès, Aurélien ; MacGrogan, Gaëtan ; Sevenet, Nicolas ; Letouzé, Eric ; Longy, Michel

Familial breast cancers (BCs) account for 10-20% of all diagnosed BCs, yet only 20% of such tumors arise in the context of a germline mutation in known tumor suppressor genes such as BRCA1 or BRCA2. The vast genetic heterogeneity which characterizes non BRCA1 and non BRCA2 (or BRCAx) families makes grouped studies impossible to perform. Next generation sequencing techniques, however, allow individual families to be studied in order to identify rare and or private mutations but the high number [...]

Menée sur des lignées cellulaires de cancer du sein triplement négatif et à l'aide de xénogreffes, cette étude identifie 4 gènes (ADNP, AP2B1, TOMM70A, ZNF326) exerçant une fonction de suppresseur de tumeurs

Identification of new tumor suppressor genes in triple-negative breast cancer

Rangel, Roberto ; Guzman-Rojas, Liliana ; Kodama, Takahiro ; Kodama, Michiko ; Newberg, Justin Y. ; Copeland, Neal G. ; Jenkins, Nancy A.

Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step Sleeping Beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to [...]

Cet article passe en revue les travaux récents ayant mis en évidence le rôle joué par l'hétérogénéité intratumorale dans l'évolution d'une tumeur, notamment dans le processus métastatique, la résistance thérapeutique et la réponse du système immunitaire

The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome

Caswell, Deborah R. ; Swanton, Charles

Background : The advent of rapid and inexpensive sequencing technology allows scientists to decipher heterogeneity within primary tumours, between primary and metastatic sites, and between metastases. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic outcomes. Discussion : Scientists are using improved sequencing technologies to characterise and address the challenge of tumour heterogeneity, which is a [...]

A partir d'échantillons tumoraux prélevés sur 198 patients atteints d'un cancer de la prostate, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation TGF-bêta, la protéine PICK1 réprime la formation de métastases osseuses

The TGF-[beta] signalling negative regulator PICK1 represses prostate cancer metastasis to bone

Dai, Yuhu ; Ren, Dong ; Yang, Qing ; Cui, Yanmei ; Guo, Wei ; Lai, Yingrong ; Du, Hong ; Lin, Chuyong ; Li, Jun ; Song, Libing ; Peng, Xinsheng

Backgroud: Constitutive activation of TGF-

Menée à l'aide de xénogreffes de lignées cellulaires de carcinome rénal à cellules claires, cette étude met en évidence le rôle joué par une endoribonucléase (MCPIP1) dans la croissance tumorale, l'angiogenèse et le processus métastatique

MCPIP1 downregulation in clear cell renal cell carcinoma promotes vascularization and metastatic progression

Marona, Paulina ; Górka, Judyta ; Mazurek, Zofia ; Wilk, Waclaw ; Rys, Janusz ; Majka, Marcin ; Jura, Jolanta ; Miekus, Katarzyna

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL-6, IL-1 and IL-12. MCPIP1 is also a negative regulator of NF

Menée à l'aide de deux modèles murins transgéniques de cancer du sein, cette étude met en évidence des mécanismes par lesquels la protéine LOXL2 favorise la formation de métastases pulmonaires

Lysyl oxidase-like protein LOXL2 promotes lung metastasis of breast cancer

Salvador, Fernando ; Martin, Alberto ; López-Menéndez, Celia ; Moreno-Bueno, Gema ; Santos, Vanesa ; Vazquez-Naharro, Alberto ; Santamaría, Patricia G. ; Morales, Saleta ; Dubus, Pierre ; Muinelo-Romay, Laura ; López López, Rafael ; Tung, Jason C. ; Weaver, Valerie M. ; Portillo, Francisco ; Cano, Amparo

The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor [...]

Menée in vitro et in vivo sur des modèles de cancer du sein, cette étude met en évidence des mécanismes par lesquels, en activant une infiltration macrophagique, la protéine Kindlin-2 favorise le processus métastatique

Kindlin-2 regulates the growth of breast cancer tumors by activating CSF-1-mediated macrophage infiltration

Sossey-Alaoui, Khalid ; Pluskota, Elzbieta ; Bialkowska, Katarzyna ; Szpak, Dorota ; Parker, Yvonne ; Morrison, Chevaun ; Lindner, Daniel J. ; Schiemann, William P. ; Plow, Edward F.

Interplay between tumor cells and host cells in the tumor microenvironment dictates the development of all cancers. In breast cancer, malignant cells educate host macrophages to adopt a pro-tumorigenic phenotype. In this study, we show how the integrin regulatory protein kindlin-2 (FERMT2) promotes metastatic progression of breast cancer through the recruitment and subversion of host macrophages. Kindlin-2 expression was elevated in BC biopsy tissues where its levels correlated with reduced [...]

Cet article passe en revue les travaux récents sur le rôle joué par divers longs ARNs non codants dans la cancérogenèse

Long Noncoding RNA and Cancer: A New Paradigm

Bhan, Arunoday ; Soleimani, Milad ; Mandal, Subhrangsu S.

In addition to mutations or aberrant expression in the protein-coding genes, mutations and misregulation of noncoding RNAs, in particular long noncoding RNAs (lncRNA), appear to play major roles in cancer. Genome-wide association studies of tumor samples have identified a large number of lncRNAs associated with various types of cancer. Alterations in lncRNA expression and their mutations promote tumorigenesis and metastasis. LncRNAs may exhibit tumor-suppressive and -promoting (oncogenic) [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels le microenvironnement tumoral régule l'angiogenèse

Microenvironmental regulation of tumour angiogenesis

De Palma, Michele ; Biziato, Daniela ; Petrova, Tatiana V.

Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic [...]