Cet article passe en revue les travaux récents ayant mis en évidence une hétérogénéité génomique et épigénomique chez des patients atteints d'une leucémie lymphocytaire chronique

Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

Guièze, Romain ; Wu, Catherine J.

Defining features of chronic lymphocytic leukemia (CLL) are not only its immunophenotype of CD19+CD5+CD23+sIgdim expressing clonal mature B cells but also its highly variable clinical course. In recent years, advances in massively parallel sequencing technologies have led to rapid progress in our understanding of the CLL genome and epigenome. Overall, these studies have clearly demarcated not only the vast degree of genetic and epigenetic heterogeneity amongst individuals with CLL but also even [...]

A partir d'échantillons sanguins prélevés de façon séquentielle sur un patient atteint d'un myélome multiple, cette étude évalue la faisabilité d'une technique combinant cartographie optique et séquençage de l'ADN pour mettre en évidence des variants structuraux du génome tumoral

Single-molecule analysis reveals widespread structural variation in multiple myeloma

Gupta, Aditya ; Place, Michael ; Goldstein, Steven ; Sarkar, Deepayan ; Zhou, Shiguo ; Potamousis, Konstantinos ; Kim, Jaehyup ; Flanagan, Claire ; Li, Yang ; Newton, Michael A. ; Callander, Natalie S. ; Hematti, Peiman ; Bresnick, Emery H. ; Ma, Jian ; Asimakopoulos, Fotis ; Schwartz, David C.

Multiple myeloma (MM), a malignancy of plasma cells, is characterized by widespread genomic heterogeneity and, consequently, differences in disease progression and drug response. Although recent large-scale sequencing studies have greatly improved our understanding of MM genomes, our knowledge about genomic structural variation in MM is attenuated due to the limitations of commonly used sequencing approaches. In this study, we present the application of optical mapping, a single-molecule, [...]

A partir d'échantillons de tissu tumoral et de tissu sain prélevés sur 42 patients atteints d'un cancer du côlon de stade II, puis validée sur des bases de données portant sur 553 échantillons complémentaires, cette étude identifie la présence de mutations du gène AMER1 dans quelque 10% des cas

Exome sequencing reveals AMER1 as a frequently mutated gene in colorectal cancer

Sanz-Pamplona, Rebeca ; López-Doriga, Adriana ; Pare-Brunet, Laia ; Lazaro, Kira ; Bellido, Fernando ; Alonso, M. Henar ; Aussó, Susanna ; Guino, Elisabeth ; Beltran, Sergi ; Castro-Giner, Francesc ; Gut, Marta ; Sanjuan, Xavier ; Closa, Adria ; Cordero, David ; Moron-Duran, Francisco D. ; Soriano, Antonio ; Salazar, Ramon ; Valle, Laura ; Moreno, Víctor

PURPOSE: Somatic mutations occur at early stages of adenoma and accumulate throughout colorectal cancer (CRC) progression. The aim of this study was to characterize the mutational landscape of stage II tumors and to search for novel recurrent mutations likely implicated in CRC tumorigenesis. DESIGN: The exomic DNA of 42 stage II, microsatellite stable, colon tumors and their paired mucosae were sequenced. Other molecular data available in the discovery dataset (gene expression, methylation, and [...]

Menée à l'aide d'une technique de séquençage profond sur 276 échantillons tumoraux prélevés sur des patients atteints d'un neuroblastome, cette étude identifie la présence de populations sous-clonales présentant des mutations du gène ALK

Deep sequencing reveals occurrence of sub-clonal ALK mutations in neuroblastoma at diagnosis

Bellini, Angela ; Bernard, Virginie ; Leroy, Quentin ; Rio-Frio, Thomas ; Pierron, Gaëlle ; Combaret, Valerie ; Lapouble, Eve ; Clement, Nathalie ; Rubie, Herve ; Thebaud, Estelle ; Chastagner, Pascal ; Defachelles, Anne Sophie ; Bergeron, Christophe ; Buchbinder, Nimrod ; Taque, Sophie ; Auvrignon, Anne ; Valteau-Couanet, Dominique ; Michon, Jean ; Janoueix-Lerosey, Isabelle ; Delattre, Olivier ; Schleiermacher, Gudrun

PURPOSE: In neuroblastoma (NB), activating ALK receptor tyrosine kinase point mutations play a major role in oncogenesis. We explored the potential occurrence of ALK mutations at a subclonal level using targeted deep sequencing. EXPERIMENTAL DESIGN: In a clinically representative series of 276 diagnostic NB samples, exons 23 and 25 of the ALK gene, containing the F1174 and R1275 mutation hotspots, respectively, were re-sequenced with an extremely high depth of coverage. RESULTS: At the F1174 [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, sous la régulation d'un long ARN non codant (PCA3), PRUNE2 exerce une fonction de suppresseur de tumeurs dans le cancer de la prostate

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Salameh, Ahmad ; Lee, Alessandro K. ; Cardó-Vila, Marina ; Nunes, Diana N. ; Efstathiou, Eleni ; Staquicini, Fernanda I. ; Dobroff, Andrey S. ; Marchiò, Serena ; Navone, Nora M. ; Hosoya, Hitomi ; Lauer, Richard C. ; Wen, Sijin ; Salmeron, Carolina C. ; Hoang, Anh ; Newsham, Irene ; Lima, Leandro A. ; Carraro, Dirce M. ; Oliviero, Salvatore ; Kolonin, Mikhail G. ; Sidman, Richard L. ; Do, Kim-Anh ; Troncoso, Patricia ; Logothetis, Christopher J. ; Brentani, Ricardo R. ; Calin, George A. ; Cavenee, Webster K. ; Dias-Neto, Emmanuel ; Pasqualini, Renata ; Arap, Wadih

Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent [...]

Menée sur des lignées cellulaires de cancer colorectal, cette étude met en évidence des mécanismes par lesquels le facteur de transcription ZBED6 régule la croissance des cellules tumorales

Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells

Akhtar Ali, Muhammad ; Younis, Shady ; Wallerman, Ola ; Gupta, Rajesh ; Andersson, Leif ; Sjöblom, Tobias

The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer [...]

Menée sur des lignées cellulaires de cancer du sein, cette étude met en évidence des mécanismes par lesquels, en fonction de la présence ou de l'absence de mutations du gène TP53, l'activation du récepteur TRL4 régule de façon différente la croissance des cellules tumorales

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan, Svasti ; Brown, Powel

Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30–50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type [...]

Menée sur des lignées cellulaires et à l'aide de bases de données portant sur des patientes atteintes d'un cancer du sein, cette étude met en évidence des mécanismes par lesquels la protéine kinase DAPK1 favorise la croissance des tumeurs présentant un gène P53 muté

Death-associated protein kinase 1 promotes growth of p53-mutant cancers

Zhao, Jing ; Zhao, Dekuang ; Poage, Graham M. ; Mazumdar, Abhijit ; Zhang, Yun ; Hill, Jamal L. ; Hartman, Zachary C. ; Savage, Michelle I. ; Mills, Gordon B. ; Brown, Powel H.

Estrogen receptor–negative (ER-negative) breast cancers are extremely aggressive and associated with poor prognosis. In particular, effective treatment strategies are limited for patients diagnosed with triple receptor–negative breast cancer (TNBC), which also carries the worst prognosis of all forms of breast cancer; therefore, extensive studies have focused on the identification of molecularly targeted therapies for this tumor subtype. Here, we sought to identify molecular targets that are [...]

Menée à l'aide de modèles murins d'épendymome, cette étude identifie 8 oncogènes et 10 gènes suppresseurs de tumeurs

An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes

Mohankumar, Kumarasamypet M. ; Currle, David S. ; White, Elsie ; Boulos, Nidal ; Dapper, Jason ; Eden, Christopher ; Nimmervoll, Birgit ; Thiruvenkatam, Radhika ; Connelly, Michele ; Kranenburg, Tanya A. ; Neale, Geoffrey ; Olsen, Scott ; Wang, Yong-Dong ; Finkelstein, David ; Wright, Karen ; Gupta, Kirti ; Ellison, David W. ; Thomas, Arzu Onar ; Gilbertson, Richard J.

Cancers are characterized by non-random chromosome copy number alterations that presumably contain oncogenes and tumor-suppressor genes (TSGs). The affected loci are often large, making it difficult to pinpoint which genes are driving the cancer. Here we report a cross-species in vivo screen of 84 candidate oncogenes and 39 candidate TSGs, located within 28 recurrent chromosomal alterations in ependymoma. Through a series of mouse models, we validate eight new ependymoma oncogenes and ten new [...]

Menée à l'aide de modèles murins et de lignées cellulaires, cette étude met en évidence des mécanismes permettant de rendre compte de la fonction de suppresseur de tumeurs attribuée au facteur de transcription GRLH3 dans les carcinomes épidermoïdes de la tête et du cou

Identification of a Novel Proto-oncogenic Network in Head and Neck Squamous Cell Carcinoma

Georgy, Smitha R. ; Cangkrama, Michael ; Srivastava, Seema ; Partridge, Darren ; Auden, Alana ; Dworkin, Sebastian ; McLean, Catriona A. ; Jane, Stephen M. ; Darido, Charbel

Background: The developmental transcription factor Grainyhead-like 3 (GRHL3) plays a critical tumor suppressor role in the mammalian epidermis through direct regulation of PTEN and the PI3K/AKT/mTOR signaling pathway. GRHL3 is highly expressed in all tissues derived from the surface ectoderm, including the oral cavity, raising a question about its potential role in suppression of head and neck squamous cell carcinoma (HNSCC). Methods: We explored the tumor suppressor role of Grhl3 in HNSCC [...]

Cet article passe en revue les travaux récents sur le rôle joué par la signalisation Akt/PKB dans le microenvironnement tumoral pour favoriser l'échappement au système immunitaire

Integrated Akt/PKB Signaling in Immunomodulation and Its Potential Role in Cancer Immunotherapy

Xue, Gongda ; Zippelius, Alfred ; Wicki, Andreas ; Mandalà, Mario ; Tang, Fengyuan ; Massi, Daniela ; Hemmings, Brian A.

T cell development and maturation involve a variety of defined and coordinated developmental stages under the control of a variety of signaling networks. They function as the major mediator in cell-based immunity that defends against pathogen infections and executes immune surveillance against tumor cells. Protein kinase B (PKB, also called Akt) is central to multiple signaling pathways and transduces extracellular signals to dictate cellular responses towards proliferation, migration, [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le co-facteur de transcription TBL1 régule la prolifération cellulaire dans un adénocarcinome canalaire du pancréas

Transcriptional co-factor Transducin beta-like (TBL) 1 acts as a checkpoint in pancreatic cancer malignancy

Stoy, Christian ; Sundaram, Aishwarya ; Rios Garcia, Marcos ; Wang, Xiaoyue ; Seibert, Oksana ; Zota, Annika ; Wendler, Susann ; Männle, David ; Hinz, Ulf ; Sticht, Carsten ; Muciek, Maria ; Gretz, Norbert ; Rose, Adam J. ; Greiner, Vera ; Hofmann, Thomas G. ; Bauer, Andrea ; Hoheisel, Jorg ; Berriel Diaz, Mauricio ; Gaida, Matthias M. ; Werner, Jens ; Schafmeier, Tobias ; Strobel, Oliver ; Herzig, Stephan

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here, we show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine PDAC. Inactivation of [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en activant la voie de signalisation TGF-bêta, la protéine ITGBL1 favorise la formation de métastases osseuses d'une tumeur du sein

ITGBL1 is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGF-β Signaling Pathway

Li, Xiao-Qing ; Du, Xin ; Li, Dong-Mei ; Kong, Peng-Zhou ; Sun, Yan ; Liu, Pei-Fang ; Wang, Qing-Shan ; Feng, Yu-Mei

Bone metastasis affects over 70% of advanced breast cancer patients, but the molecular mechanisms of this process remain unclear. Here we present clinical and experimental evidence to clarify the role of the integrin β-like 1 (ITGBL1) as a key contributor to bone metastasis of breast cancer. In an in vivo model system and in vitro experiments, ITGBL1 expression promoted formation of osteomimetic breast cancers, facilitating recruitment, residence and growth of cancer cells in bone [...]

A partir d'une analyse de la littérature, cette étude évalue les coûts annuels induits par des travaux de recherche préclinique non reproductibles aux Etats-Unis

The Economics of Reproducibility in Preclinical Research

Freedman, Leonard P. ; Cockburn, Iain M. ; Simcoe, Timothy S.

Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total) prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B)/year spent on preclinical research that is not reproducible—in the United States alone. We outline a framework for solutions and a plan for [...]