Cet article décrit des critères conceptuels à mettre en oeuvre pour attribuer l'origine de réarrangements chromosomiques à un phénomène de chromothripsis

Criteria for Inference of Chromothripsis in Cancer Genomes

Korbel, Jan O ; Campbell, Peter J

Chromothripsis scars the genome when localized chromosome shattering and repair occurs in a one-off catastrophe. Outcomes of this process are detectable as massive DNA rearrangements affecting one or a few chromosomes. Although recent findings suggest a crucial role of chromothripsis in cancer development, the reproducible inference of this process remains challenging, requiring that cataclysmic one-off rearrangements be distinguished from localized lesions that occur progressively. We describe [...]

A partir d'échantillons prélevés sur 341 patients atteints d'une leucémie lymphocytaire chronique, cette étude met en évidence des mutations somatiques du gène POT1, impliqué dans le fonctionnement des télomères

POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia

Ramsay, Andrew J. ; Quesada, Victor ; Foronda, Miguel ; Conde, Laura ; Martinez-Trillos, Alejandra ; Villamor, Neus ; Rodriguez, David ; Kwarciak, Agnieszka ; Garabaya, Cecilia ; Gallardo, Mercedes ; Lopez-Guerra, Monica ; Lopez-Guillermo, Armando ; Puente, Xose S. ; Blasco, Maria A. ; Campo, Elias ; López-Otín, Carlos

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. We have analyzed exome sequencing data from 127 individuals with CLL and Sanger sequencing data from 214 additional affected individuals, identifying recurrent somatic mutations in POT1 (encoding protection of telomeres 1) in 3.5% of the cases, with the frequency reaching 9% when only individuals without IGHV@ mutations were considered. POT1 encodes a component of the shelterin complex and is the first member of this [...]

A partir de données de séquençage obtenues sur des tumeurs du pancréas, cette étude évalue les performances d'un algorithme visant à attribuer l'origine des réarrangements d'une région chromosomique à des cycles de cassure-fusion-pont

An algorithmic approach for breakage-fusion-bridge detection in tumor genomes

Zakov, Shay ; Kinsella, Marcus ; Bafna, Vineet

Breakage-fusion-bridge (BFB) is a mechanism of genomic instability characterized by the joining and subsequent tearing apart of sister chromatids. When this process is repeated during multiple rounds of cell division, it leads to patterns of copy number increases of chromosomal segments as well as fold-back inversions where duplicated segments are arranged head-to-head. These structural variations can then drive tumorigenesis. BFB can be observed in progress using cytogenetic techniques, but [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du gène NKX2-1, le micro-ARN 365 joue un rôle dans la prolifération des cellules de cancer du poumon

MicroRNA-365 Regulates NKX2-1, a Key Mediator of Lung Cancer

Kang, Sung-Min ; Lee, Heon-Jin ; Cho, Je-Yoel

MicroRNAs constitute a class of small noncoding RNAs that play roles in tumorigenesis. We found that NKX2-1 protein levels were generally high in the lung cancer tissues whereas miRNA-365 expression levels were down-regulated. Ectopic miR-365 expression decreased NKX2-1 expression in lung cancer cell lines. Transfection of a miR-365 mimic led to reduced proliferation of lung cancer cells; conversely, a miR-365 inhibitor slightly increased cell proliferation. The NKX2-1 overexpression [...]

A partir de 2 093 échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, puis menée in vitro, cette étude met en évidence le rôle de suppresseur de tumeurs joué par le gène CHD1, localisé sur la région chromosomique 5q21

CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer

Burkhardt, Lia ; Fuchs, Sarah ; Krohn, Antje ; Kluth, Martina ; Bachmann, Frederik ; Huland, Hartwig ; Steuber, Thomas ; Graefen, Markus ; Schlomm, Thorsten ; Minner, Sarah ; Sauter, Guido ; Sirma, Hüseyin ; Simon, Ronald ; Masser, Sawinee ; Mader, Malte

Deletions involving the chromosomal band 5q21 are among the most frequent alterations in prostate cancer. Using SNP arrays, we mapped a 1.3 megabase minimally deleted region including only the RGMB and CHD1 genes. Functional analyses demonstrated that CHD1 is an essential tumor suppressor. FISH analysis of 2,093 prostate cancers revealed a strong association between CHD1 deletion, PSA biochemical failure (p=0.0038) and absence of ERG fusion (p<0.0001). We found that inactivation of CHD1 in [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels l'épériguline et les fibroblastes associés aux tumeurs régulent la croissance tumorale de néoplasies associées à une colite

Tumor fibroblast–derived epiregulin promotes growth of colitis-associated neoplasms through ERK

Neufert, Clemens ; Becker, Christoph ; xFc, ; reci, ; xD, ; zlem, ; Waldner, Maximilian J. ; Backert, Ingo ; Floh, Katharina ; Atreya, Imke ; Leppkes, Moritz ; Jefremow, Andre ; Vieth, Michael ; Schneider-Stock, Regine ; Klinger, Patricia ; Greten, Florian R. ; Threadgill, David W. ; Sahin, Ugur ; Neurath, Markus F.

Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated [...]

Menée in vitro, cette étude met en évidence des profils différents d'expression des glycosphingolipides dans les cellules souches de cancer du sein par rapport aux autres cellules cancéreuses

Differential expression profiles of glycosphingolipids in human breast cancer stem cells vs. cancer non-stem cells

Liang, Yuh-Jin ; Ding, Yao ; Levery, Steven B. ; Lobaton, Marlin ; Handa, Kazuko ; Hakomori, Sen-itiroh

Previous studies demonstrated that certain glycosphingolipids (GSLs) are involved in various cell functions, such as cell growth and motility. Recent studies showed changes in GSL expression during differentiation of human embryonic stem cells; however, little is known about expression profiles of GSLs in cancer stem cells (CSCs). CSCs are a small subpopulation in cancer and are proposed as cancer-initiating cells, have been shown to be resistant to numerous chemotherapies, and may cause cancer [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels les protéines inhibitrices de l'apoptose régulent la migration cellulaire ainsi que les processus invasif et métastatique

Regulation of cell migration, invasion and metastasis by IAP proteins and their antagonists

Fulda, S.

Inhibitor of apoptosis (IAP) proteins are a family comprised of a total of eight mammalian members that were initially described to act as endogenous inhibitors of caspases. In addition, extensive evidence has been accumulated over the last years showing that IAP proteins can regulate various signal transduction pathways, thereby exerting non-apoptotic functions beyond the inhibition of apoptosis. For example, IAP proteins have been implied in the control of cell motility, migration, invasion [...]

Cet article passe en revue les travaux récents sur les mécanismes d'action du facteur dérivé de l'épithélium pigmentaire et évalue leur intérêt pour le développement de traitements du cancer

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

Becerra, S. Patricia ; Notario, Vicente

The potent actions of pigment epithelium-derived factor (PEDF) on tumour-associated cells, and its extracellular localization and secretion, stimulated research on this multifunctional serpin. Such studies have identified several PEDF receptors and downstream signalling pathways. Known cellular PEDF responses have expanded from the initial discovery that PEDF induces retinoblastoma cell differentiation to its anti-angiogenic, antitumorigenic and antimetastatic properties. Although the diversity [...]

Menée sur des échantillons de tumeurs primitives et de métastases prélevés sur 9 patientes atteintes d'un cancer séreux de l'ovaire, cette étude met en évidence des micro-ARNs dont le niveau d'expression est élevé de façon préférentielle dans les lésions métastatiques

Identification of Ovarian Cancer Metastatic miRNAs

Vang, Souriya ; Wu, Hsin-Ta ; Fischer, Andrew ; Miller, Daniel H. ; MacLaughlan, Shannon ; Douglass, Elijah ; Steinhoff, Margaret ; Collins, Colin ; Smith, Peter J. S. ; Brard, Laurent ; Brodsky, Alexander S.

Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential [...]

Menée notamment à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lequels la protéine Hsp27 régule la transition épithélio-mésenchymateuse, le processus métastatique et les cellules tumorales circulantes dans le cancer de la prostate

Hsp27 regulates epithelial mesenchymal transition, metastasis and circulating tumor cells in prostate cancer

Shiota, Masaki ; Bishop, Jennifer L. ; Nip, KaMun ; Zardan, Anousheh ; Takeushi, Ario ; Cordonnier, Thomas ; Beraldi, Eliana ; Bazov, Jenny ; Fazli, Ladan ; Chi, Kim N. ; Gleave, Martin ; Zoubeidi, Amina

Defining the mechanisms underlying metastatic progression of prostate cancer (PCa) may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-to-mesenchymal transition (EMT), and the mechanisms that control the process of EMT in cancer cells are still emerging. Here we report that the molecular chaperone Hsp27 (HSPB1) drives EMT in PCa while its attenuation reverses EMT and decreases cell migration, invasion and matrix [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence des cellules de neuroblastome dotées de propriétés de cellules souches cancéreuses et suggère que des modifications épigénétiques ont contribué à leur développement

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Ikegaki, Naohiko ; Shimada, Hiroyuki ; Fox, Autumn M. ; Regan, Paul L. ; Jacobs, Joshua R. ; Hicks, Sakeenah L. ; Rappaport, Eric F. ; Tang, Xao X.

Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and half of the cases are highly aggressive. By treating NB cell lines [SKNAS, SKNBE(2)C, CHP134, and SY5Y] with epigenetic modifiers for a short time, followed by sphere-forming culture conditions, we have established stem cell–like NB cells that are phenotypically stable for more than a year. These cells are characterized by their [...]

Cet article présente une méthode pour cartographier, à l'échelle d'un nucléotide, les cassures de l'ADN double brin à l'aide des techniques de séquençage de nouvelle génération

Nucleotide-resolution DNA double-strand break mapping by next-generation sequencing

Crosetto, Nicola ; Mitra, Abhishek ; Silva, Maria Joao ; Bienko, Magda ; Dojer, Norbert ; Wang, Qi ; Karaca, Elif ; Chiarle, Roberto ; Skrzypczak, Magdalena ; Ginalski, Krzysztof ; Pasero, Philippe ; Rowicka, Maga ; Dikic, Ivan

We present a genome-wide approach to map DNA double-strand breaks (DSBs) at nucleotide resolution by a method we termed BLESS (direct in situ breaks labeling, enrichment on streptavidin and next-generation sequencing). We validated and tested BLESS using human and mouse cells and different DSBs-inducing agents and sequencing platforms. BLESS was able to detect telomere ends, Sce endonuclease–induced DSBs and complex genome-wide DSB landscapes. As a proof of principle, we characterized the [...]

Cet article présente un modèle, établi à l'aide de xénogreffes, de réaction leucémoïde transitoire progressant en leucémie myéloïde chez les patients présentant une trisomie 21

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome

Saida, Satoshi ; Watanabe, Ken-ichiro ; Sato-Otsubo, Aiko ; Terui, Kiminori ; Yoshida, Kenichi ; Okuno, Yusuke ; Toki, Tsutomu ; Wang, RuNan ; Shiraishi, Yuichi ; Miyano, Satoru ; Kato, Itaru ; Morishima, Tatsuya ; Fujino, Hisanori ; Umeda, Katsutsugu ; Hiramatsu, Hidefumi ; Adachi, Souichi ; Ito, Etsuro ; Ogawa, Seishi ; Ito, Mamoru ; Nakahata, Tatsutoshi ; Heike, Toshio

Transient abnormal myelopoiesis (TAM) is a clonal pre-leukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, IL-2Rγnull mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy [...]