Cet article passe en revue le rôle des anomalies de nombres de copies de gènes dans les maladies humaines et analyse les perspectives offertes par des thérapies ciblant les effets de ces anomalies

Gene Copy-Number Alterations: A Cost-Benefit Analysis

Tang, Yun-Chi ; Amon, Angelika

Changes in DNA copy number, whether confined to specific genes or affecting whole chromosomes, have been identified as causes of diseases and developmental abnormalities and as sources of adaptive potential. Here, we discuss the costs and benefits of DNA copy-number alterations. Changes in DNA copy number are largely detrimental. Amplifications or deletions of specific genes can elicit discrete defects. Large-scale changes in DNA copy number can also cause detrimental phenotypes that are due to [...]

Cet article passe en revue les travaux récents sur les avantages et les limites des techniques de séquençage à haut débit pour identifier des gènes de fusion associés au cancer

Fusion genes and their discovery using high throughput sequencing

Annala, M. ; Parker, B. ; Zhang, W. ; Nykter, M.

Fusion genes are hybrid genes that combine parts of two or more original genes. They can form as a result of chromosomal rearrangements or abnormal transcription, and have been shown to act as drivers of malignant transformation and progression in many human cancers. The biological significance of fusion genes together with their specificity to cancer cells has made them into excellent targets for molecular therapy. Fusion genes are also used as diagnostic and prognostic markers to confirm [...]

Cet article passe en revue les travaux récents sur les mécanismes associés aux translocations chromosomiques dans les lymphocytes et sur les voies de signalisation spécialisées dans la réparation des cassures double brin de l'ADN

Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System

Alt, Frederick W ; Zhang, Yu ; Meng, Fei-Long ; Guo, Chunguang ; Schwer, Bjoern

Chromosomal translocations involving antigen receptor loci are common in lymphoid malignancies. Translocations require DNA double-strand breaks (DSBs) at two chromosomal sites, their physical juxtaposition, and their fusion by end-joining. Ability of lymphocytes to generate diverse repertoires of antigen receptors and effector antibodies derives from programmed genomic alterations that produce DSBs. We discuss these lymphocyte-specific processes, with a focus on mechanisms that provide [...]

Menée sur 138 patients atteints d'une leucémie lymphoblastique aiguë récidivante, cette étude met en évidence le rôle de mutations activatrices du gène NT5C2 dans la résistance à une chimiothérapie à l'aide d'analogues de nucléosides

Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Tzoneva, Gannie ; Perez-Garcia, Arianne ; Carpenter, Zachary ; Khiabanian, Hossein ; Tosello, Valeria ; Allegretta, Maddalena ; Paietta, Elisabeth ; Racevskis, Janis ; Rowe, Jacob M. ; Tallman, Martin S. ; Paganin, Maddalena ; Basso, Giuseppe ; Hof, Jana ; Kirschner-Schwabe, Renate ; Palomero, Teresa ; Rabadan, Raul ; Ferrando, Adolfo

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the [...]

Menée sur 10 patients pédiatriques atteints d'une leucémie lymphoblastique récidivante, cette étude suggère que des mutations dans le gène NTS5C2 sont associées à la résistance aux traitements à l'aide d'analogues de nucléosides

Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia

Meyer, Julia A. ; Wang, Jinhua ; Hogan, Laura E. ; Yang, Jun J. ; Dandekar, Smita ; Patel, Jay P. ; Tang, Zuojian ; Zumbo, Paul ; Li, Sheng ; Zavadil, Jiri ; Levine, Ross L. ; Cardozo, Timothy ; Hunger, Stephen P. ; Raetz, Elizabeth A. ; Evans, William E. ; Morrison, Debra J. ; Mason, Christopher E. ; Carroll, William L.

Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial [...]

Menée sur des échantillons sanguins prélevés sur 206 patients pédiatriques atteints d'une leucémie myéloïde aiguë, cette étude analyse la distribution de mutations de 19 gènes impliqués dans la régulation épigénétique

Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2 and DNMT3A

Liang, Der-Cherng ; Liu, Hsi-Che ; Yang, Chao-Ping ; Jaing, Tang-Her ; Hung, Iou-Jih ; Yeh, Ting-Chi ; Chen, Shih-Hsiang ; Hou, Jen-Yin ; Huang, Ying-Jung ; Shih, Yu-Shu ; Huang, Yu-Hui ; Lin, Tung-Huei ; Shih, Lee-Yung

Genes involving epigenetic regulators have recently been described in adult AML. Similar studies are limited in children. We analyzed gene mutations and cooperation in pediatric AML with special reference on mutated epigenetic regulators. Nineteen gene mutations including 8 class I genes, 4 class II genes, WT1 and TP53 (class III), and 5 epigenetic regulator genes (class IV), were analyzed in 206 children with de novo AML. Mutational analysis was performed with PCR-based assay followed by [...]

Menée sur des échantillons tumoraux prélevés sur 392 patients chinois atteints d'un cancer du poumon non à petites cellules, cette étude évalue la prévalence et les caractéristiques des fusions du proto-oncogène RET

KIF5B-RET fusions in Chinese patients with non–small cell lung cancer

Cai, Weijing ; Su, Chunxia ; Li, Xuefei ; Fan, Lihong ; Zheng, Limou ; Fei, Ke ; Zhou, Caicun

BACKGROUND: It has been established that “ret proto-oncogene” (RET) fusions are oncogenic drivers in non–small cell lung cancer (NSCLC). The prevalence and clinicopathologic characteristics of RET fusions in Chinese patients with NSCLC remain unclear. The objective of the current study was to determine the prevalence and clinicopathologic characteristics of KIF5B-RET fusions (fusions of the RET and kinesin family member 5B [KIF5B] genes) in Chinese patients with NSCLC. METHODS: The authors [...]

Menée sur des échantillons tumoraux prélevés sur 57 patientes atteintes d'un carcinome séreux de l'utérus, cette étude met en évidence la distribution des mutations somatiques d'un ensemble de gènes impliqués dans la réparation de l'ADN, le remodelage de la chromatine, le cycle et la prolifération cellulaires

Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

Zhao, Siming ; Choi, Murim ; Overton, John D. ; Bellone, Stefania ; Roque, Dana M. ; Cocco, Emiliano ; Guzzo, Federica ; English, Diana P. ; Varughese, Joyce ; Gasparrini, Sara ; Bortolomai, Ileana ; Buza, Natalia ; Hui, Pei ; Abu-Khalaf, Maysa ; Ravaggi, Antonella ; Bignotti, Eliana ; Bandiera, Elisabetta ; Romani, Chiara ; Todeschini, Paola ; Tassi, Renata ; Zanotti, Laura ; Carrara, Luisa ; Pecorelli, Sergio ; Silasi, Dan-Arin ; Ratner, Elena ; Azodi, Masoud ; Schwartz, Peter E. ; Rutherford, Thomas J. ; Stiegler, Amy L. ; Mane, Shrikant ; Boggon, Titus J. ; Schlessinger, Joseph ; Lifton, Richard P. ; Santin, Alessandro D.

Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la protéine kinase PKC

Control of Nutrient Stress-Induced Metabolic Reprogramming by PKC

Ma, Li ; Tao, Yongzhen ; Duran, Angeles ; Llado, Victoria ; Galvez, Anita ; Barger, Jennifer F ; Castilla, Elias A ; Chen, Jing ; Yajima, Tomoko ; Porollo, Aleksey ; Medvedovic, Mario ; Brill, Laurence M ; Plas, David R ; Riedl, Stefan J ; Leitges, Michael ; Diaz-Meco, Maria T ; Richardson, Adam D ; Moscat, Jorge

Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKC

Cet article passe en revue les travaux récents sur le rôle de la télomérase dans les cellules souches et la cancérogenèse

The Role of Telomeres in Stem Cells and Cancer

Günes, Cagatay ; Rudolph, K.  Lenhard

Telomere shortening impairs proliferation of transformed cells but also leads to cancer initiation by inducing chromosomal instability. Here, we discuss recent developments in our understanding of the role of telomeres in replication stress and how telomerase expression in somatic stem cells may affect genome integrity control and carcinogenesis.

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par le micro-ARN 18b dans la progression d'un mélanome

The Role of miR-18b in MDM2-p53 Pathway Signaling and Melanoma Progression

Dar, Altaf A ; Majid, Shahana ; Rittsteuer, Claudia ; De Semir, David ; Bezrookove, Vladimir ; Tong, Schuyler ; Nosrati, Mehdi ; Sagebiel, Richard ; Miller, James R. ; Kashani-Sabet, Mohammed

Background Although p53 is inactivated by point mutations in many tumors, melanomas infrequently harbor mutations in the p53 gene. Here we investigate the biological role of microRNA-18b (miR-18b) in melanoma by targeting the MDM2-p53 pathway. Methods Expression of miR-18b was examined in nevi (n = 48) and melanoma (n = 92) samples and in melanoma cell lines and normal melanocytes. Immunoblotting was performed to determine the expression of various proteins regulated by miR-18b. The effects of [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en secrétant une forme soluble de la protéine Jagged-1, des cellules endothéliales activent la signalisation Notch et favorisent la formation de cellules souches d'un cancer colorectal

Endothelial Cells Promote the Colorectal Cancer Stem Cell Phenotype through a Soluble Form of Jagged-1

Lu, Jia ; Ye, Xiangcang ; Fan, Fan ; Xia, Ling ; Bhattacharya, Rajat ; Bellister, Seth ; Tozzi, Federico ; Sceusi, Eric ; Zhou, Yunfei ; Tachibana, Isamu ; Maru, Dipen M ; Hawke, David H ; Rak, Janusz ; Mani, Sendurai ; Zweidler-McKay, Patrick ; Ellis, Lee M

We report a paracrine effect whereby endothelial cells (ECs) promote the cancer stem cell (CSC) phenotype of human colorectal cancer (CRC) cells. We showed that, without direct cell-cell contact, ECs secrete factors that promoted the CSC phenotype in CRC cells via Notch activation. In human CRC specimens, CD133 and Notch intracellular domain-positive CRC cells colocalized in perivascular regions. An EC-derived, soluble form of Jagged-1, via ADAM17 proteolytic activity, led to Notch activation [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel deux cytokines des lymphocytes auxiliaires 1, l'interféron gamma et le facteur de nécrose tumorale, induisent une sénescence des cellules cancéreuses

T-helper-1-cell cytokines drive cancer into senescence

Braumuller, Heidi ; Wieder, Thomas ; Brenner, Ellen ; Aszmann, Sonja ; Hahn, Matthias ; Alkhaled, Mohammed ; Schilbach, Karin ; Essmann, Frank ; Kneilling, Manfred ; Griessinger, Christoph ; Ranta, Felicia ; Ullrich, Susanne ; Mocikat, Ralph ; Braungart, Kilian ; Mehra, Tarun ; Fehrenbacher, Birgit ; Berdel, Julia ; Niessner, Heike ; Meier, Friedegund ; van den Broek, Maries ; Haring, Hans-Ulrich ; Handgretinger, Rupert ; Quintanilla-Martinez, Leticia ; Fend, Falko ; Pesic, Marina ; Bauer, Jurgen ; Zender, Lars ; Schaller, Martin ; Schulze-Osthoff, Klaus ; Rocken, Martin

Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-

Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par l'adrénomédulline, un vasodilatateur, dans la progression d'un cancer colorectal

Expression of adrenomedullin in human colorectal tumors and its role in cell growth and invasion in vitro and in xenograft growth in vivo

Nouguerède, Emilie ; Berenguer, Caroline ; Garcia, Stéphane ; Bennani, Bahia ; Delfino, Christine ; Nanni, Isabelle ; Dahan, Laetitia ; Gasmi, Mohamed ; Seitz, Jean-François ; Martin, Pierre-Marie ; Ouafik, L'Houcine

Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). In this study, real-time quantitative reverse transcription demonstrated a significant expression of AM mRNA in tumor samples from colorectal cancer (CRC) patients in clinical stage II, III, and IV when compared with normal colorectal tissue. AM, CLR, RAMP2, and RAMP3 proteins were [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la protéine CDCP1 dans la régulation du processus métastatique d'un carcinome rénal à cellules claires

Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients

Emerling, Brooke M. ; Benes, Cyril H. ; Poulogiannis, George ; Bell, Eric L. ; Courtney, Kevin ; Liu, Hui ; Choo-Wing, Rayman ; Bellinger, Gary ; Tsukazawa, Kazumi S. ; Brown, Victoria ; Signoretti, Sabina ; Soltoff, Stephen P. ; Cantley, Lewis C.

CUB domain-containing protein 1 (CDCP1) is a transmembrane protein that is highly expressed in stem cells and frequently overexpressed and tyrosine-phosphorylated in cancer. CDCP1 promotes cancer cell metastasis. However, the mechanisms that regulate CDCP1 are not well-defined. Here we show that hypoxia induces CDCP1 expression and tyrosine phosphorylation in hypoxia-inducible factor (HIF)-2α–, but not HIF-1α–, dependent fashion. shRNA knockdown of CDCP1 impairs cancer cell migration under [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'expression du gène FOXC2 dans l'activation d'une transition épithélio-mésenchymateuse et le processus métastatique d'un cancer du sein

FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer

Hollier, Brett G. ; Tinnirello, Agata A. ; Werden, Steven J. ; Evans, Kurt W. ; Taube, Joseph H. ; Sarkar, Tapasree Roy ; Sphyris, Nathalie ; Shariati, Maryam ; Kumar, Sreedevi V. ; Battula, Venkata L. ; Herschkowitz, Jason I. ; Guerra, Rudy ; Chang, Jeffrey T. ; Miura, Naoyuki ; Rosen, Jeffrey M. ; Mani, Sendurai A.

Resistance to chemotherapy and metastases are the major causes of breast cancer-related mortality. Moreover, cancer stem cells (CSCs) play critical roles in cancer progression and treatment resistance. Previously, it was found that CSC-like cells can be generated by aberrant activation of EMT, thereby making anti-EMT strategies a novel therapeutic option for treatment of aggressive breast cancers. Here, we report that the transcription factor FOXC2 induced in response to multiple EMT signaling [...]

Cet article passe en revue les divers outils permettant de visualiser les données de génomique des cancers produites par les projets "International Cancer Genome Consortium" et "The Cancer Genome Atlas"

Visualizing multidimensional cancer genomics data

Schroeder, Michael ; Gonzalez-Perez, Abel ; Lopez-Bigas, Nuria

Cancer genomics projects employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Examples include projects carried out by the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). A crucial step in the extraction of knowledge from the data is the exploration by experts of the different alterations, as well as the multiple relationships between [...]

Cet article passe en revue les travaux récents sur l'intérêt des modèles animaux pour la compréhension des mécanismes génétiques impliqués dans les maladies humaines

Genotype to phenotype: lessons from model organisms for human genetics

Lehner, Ben

To what extent can variation in phenotypic traits such as disease risk be accurately predicted in individuals? In this Review, I highlight recent studies in model organisms that are relevant both to the challenge of accurately predicting phenotypic variation from individual genome sequences ('whole-genome reverse genetics') and for understanding why, in many cases, this may be impossible. These studies argue that only by combining genetic knowledge with in vivo measurements of biological states [...]