Menée sur une cohorte espagnole de 5 654 patients atteints d'une leucémie myélomonocytaire chronique ou d'un syndrome myélodysplasique, cette étude identifie la présence de nouvelles translocations associées et évalue leur fréquence

Reciprocal translocations in myelodysplastic syndromes and chronic myelomonocytic leukemias: Review of 5,654 patients with an evaluable karyotype

Costa, Dolors ; Muñoz, Concha ; Carrió, Ana ; Nomdedeu, Meritxell ; Calvo, Xavier ; Sole, Francesc ; Luño, Elisa ; Cervera, José ; Vallespí, Teresa ; Berneaga, Daniela ; Gómez, Cándida ; Arias, Amparo ; Such, Esperanza ; Sanz, Guillermo ; Grau, Javier ; Insunza, Andrés ; Calasanz, María J. ; Ardañaz, María T. ; Hernández, Jesús M. ; Azaceta, Gemma ; Álvarez, Sara ; Sánchez, Joaquín ; Martín, María L. ; Bargay, Joan ; Gómez, Valle ; Cervero, Carlos Javier ; Allegue, María J. ; Collado, Rosa ; Campo, Elias ; Nomdedeu, Benet ; on behalf of the Spanish Group of Myelodysplastic, Syndromes

The infrequency of translocations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemias (CMML) makes their identification and reporting interesting for the recognition of the recurrent ones and the genes involved in these neoplasias. The aims of this study were to identify new translocations associated with MDS and CMML and to establish their frequency in a cohort of 8,016 patients from the Spanish Group of MDS database. The karyotype was evaluable in 5,654 (70%) patients. [...]

Menée sur des échantillons prélevés, à quatre reprises au cours d'une période de 11 ans, sur un patient atteint d'une leucémie lymphocytaire chronique, cette étude de séquençage du génome entier met en évidence l'évolution du phénomène de chromothripsis et de sa réversibilité liée au traitement

Sporadic and reversible chromothripsis in chronic lymphocytic leukemia revealed by longitudinal genomic analysis

Bassaganyas, L. ; Bea, S. ; Escaramis, G. ; Tornador, C. ; Salaverria, I. ; Zapata, L. ; Drechsel, O. ; Ferreira, P. G. ; Rodriguez-Santiago, B. ; Tubio, J. M. C. ; Navarro, A. ; Martin-Garcia, D. ; Lopez, C. ; Martinez-Trillos, A. ; Lopez-Guillermo, A. ; Gut, M. ; Ossowski, S. ; Lopez-Otin, C. ; Campo, E. ; Estivill, X.

The general view of cancer progression is based on a gradual evolutionary process, involving a continuous acquisition of genetic changes in individual cells with successive subclonal selection and expansion. However, whole-genome sequencing (WGS) in cancer has led to discover the chromothripsis phenomenon, in which focal regions of the genome undergo extensive chromosome fragmentation and reorganization causing structural genomic complexity in some tumor cells. Chromothripsis was first [...]

Menée sur 10 échantillons de tissu provenant d'un névus mélanocytaire, cette étude évalue la proportion de cellules présentant la mutation V600E du gène BRAF

Clonal BRAF Mutations in Melanocytic Nevi and Initiating Role of BRAF in Melanocytic Neoplasia

Yeh, Iwei ; von Deimling, Andreas ; Bastian, Boris C.

BRAFV600E mutations are frequent in melanomas originating from intermittently sun-exposed skin and also in common acquired melanocytic nevi, suggesting that BRAF mutation is an early event in melanocytic neoplasia. All neoplastic melanocytes within such a nevus would be expected to carry the BRAF mutation, and thus we evaluated the frequency of cells with BRAFV600E mutations within acquired nevi by droplet digital polymerase chain reaction. In BRAF-mutant nevi the number of BRAF mutant alleles [...]

Menée sur des échantillons de tissu sain et de tissu tumoral prélevés sur 60 patients atteints d'un carcinome adénoïde kystique, cette étude met en évidence des mutations somatiques dans un ensemble de gènes, notamment de gènes impliqués dans la signalisation FGF-IGF-PI3K

The mutational landscape of adenoid cystic carcinoma

Ho, Allen S. ; Kannan, Kasthuri ; Roy, David M. ; Morris, Luc G. T. ; Ganly, Ian ; Katabi, Nora ; Ramaswami, Deepa ; Walsh, Logan A. ; Eng, Stephanie ; Huse, Jason T. ; Zhang, Jianan ; Dolgalev, Igor ; Huberman, Kety ; Heguy, Adriana ; Viale, Agnes ; Drobnjak, Marija ; Leversha, Margaret A. ; Rice, Christine E. ; Singh, Bhuvanesh ; Iyer, N. Gopalakrishna ; Leemans, C. René ; Bloemena, Elisabeth ; Ferris, Robert L. ; Seethala, Raja R. ; Gross, Benjamin E. ; Liang, Yupu ; Sinha, Rileen ; Peng, Luke ; Raphael, Benjamin J. ; Turcan, Sevin ; Gong, Yongxing ; Schultz, Nikolaus ; Kim, Seungwon ; Chiosea, Simion ; Shah, Jatin P. ; Sander, Chris ; Lee, William ; Chan, Timothy A.

Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, [...]

Menée sur 48 échantillons tumoraux prélevés sur des patients atteints d'une tumeur neuroendocrine de l'intestin grêle, cette étude met en évidence un ensemble d'anomalies génomiques somatiques

The genomic landscape of small intestine neuroendocrine tumors

Banck, Michaela S. ; Kanwar, Rahul ; Kulkarni, Amit A. ; Boora, Ganesh K. ; Metge, Franziska ; Kipp, Benjamin R. ; Zhang, Lizhi ; Thorland, Erik C. ; Minn, Kay T. ; Tentu, Ramesh ; Eckloff, Bruce W. ; Wieben, Eric D. ; Wu, Yanhong ; Cunningham, Julie M. ; Nagorney, David M. ; Gilbert, Judith A. ; Ames, Matthew M. ; Beutler, Andreas S.

Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0–0.59), mostly transitions (C>T and A>G), which [...]

Menée à l'aide d'un modèle murin, cette étude identifie un ensemble de gènes dont les mutations sont susceptibles d'être associées au développement d'une tumeur maligne des gaines des nerfs périphériques

Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis

Rahrmann, Eric P. ; Watson, Adrienne L. ; Keng, Vincent W. ; Choi, Kwangmin ; Moriarity, Branden S. ; Beckmann, Dominic A. ; Wolf, Natalie K. ; Sarver, Aaron ; Collins, Margaret H. ; Moertel, Christopher L. ; Wallace, Margaret R. ; Gel, Bernat ; Serra, Eduard ; Ratner, Nancy ; Largaespada, David A.

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 (Trp53) function and/or overexpression of human epidermal growth factor receptor (EGFR). Common insertion site (CIS) [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en régulant l'activité de la topoisomérase II

BAF complexes facilitate decatenation of DNA by topoisomerase II

Dykhuizen, Emily C. ; Hargreaves, Diana C. ; Miller, Erik L. ; Cui, Kairong ; Korshunov, Andrey ; Kool, Marcel ; Pfister, Stefan ; Cho, Yoon-Jae ; Zhao, Keji ; Crabtree, Gerald R.

Recent exon-sequencing studies of human tumours have revealed that subunits of BAF (mammalian SWI/SNF) complexes are mutated in more than 20% of all human malignancies, but the mechanisms involved in tumour suppression are unclear. BAF chromatin-remodelling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb repressive complex 2 (PRC2) across the genome. Several [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la protéine Ninj1, une molécule membranaire d'adhérence cellulaire, régule l'activité du gène suppresseur de tumeur p53

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

Cho, Seong-Jun ; Rossi, Andrea ; Jung, Yong-Sam ; Yan, Wensheng ; Liu, Gang ; Zhang, Jin ; Zhang, Min ; Chen, Xinbin

The tumor suppressor protein p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest, apoptosis, and senescence. The nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a homophilic adhesion molecule and involved in nerve regeneration. Interestingly, Ninj1 is found to be overexpressed in human cancer, but its role in tumorigenesis is not clear. Here, we found that Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage in a p53-dependent [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en régulant la sénescence induite par le gène BRAF affecté de la mutation V600E, une enzyme mitochondriale, la pyruvate déshydrogénase, joue un rôle dans le développement d'un mélanome

A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence

Kaplon, Joanna ; Zheng, Liang ; Meissl, Katrin ; Chaneton, Barbara ; Selivanov, Vitaly A. ; Mackay, Gillian ; van der Burg, Sjoerd H. ; Verdegaal, Elizabeth M. E. ; Cascante, Marta ; Shlomi, Tomer ; Gottlieb, Eyal ; Peeper, Daniel S.

In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body of evidence indicates that oncogene-induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer. Despite the widespread contribution of OIS to the cessation of [...]

Menée in vitro et à l'aide de xénogreffes de cancer du sein, cette étude met en évidence un mécanisme impliquant le récepteur EGFR dans la maturation des micro-ARNs et la réponse des cellules tumorales à un stress hypoxique

EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2

Shen, Jia ; Xia, Weiya ; Khotskaya, Yekaterina B. ; Huo, Longfei ; Nakanishi, Kotaro ; Lim, Seung-Oe ; Du, Yi ; Wang, Yan ; Chang, Wei-Chao ; Chen, Chung-Hsuan ; Hsu, Jennifer L. ; Wu, Yun ; Lam, Yung Carmen ; James, Brian P. ; Liu, Xiuping ; Liu, Chang-Gong ; Patel, Dinshaw J. ; Hung, Mien-Chie

MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in the regulation of cellular response to a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumour. However, the upstream regulators of miRNA [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la phosphorylation du gène EZH2 pour favoriser, via l'activation de la signalisation STAT3, le potentiel tumorigénique de cellules souches de glioblastome

Phosphorylation of EZH2 Activates STAT3 Signaling via STAT3 Methylation and Promotes Tumorigenicity of Glioblastoma Stem-like Cells

Kim, Eunhee ; Kim, Misuk ; Woo, Dong-Hun ; Shin, Yongjae ; Shin, Jihye ; Chang, Nakho ; Oh, Young Taek ; Kim, Hong ; Rheey, Jingeun ; Nakano, Ichiro ; Lee, Cheolju ; Joo, Kyeung Min ; Rich, Jeremy N ; Nam, Do-Hyun ; Lee, Jeongwu

Glioblastoma multiforme (GBM) displays cellular hierarchies harboring a subpopulation of stem-like cells (GSCs). Enhancer of Zeste Homolog 2 (EZH2), the lysine methyltransferase of Polycomb repressive complex 2, mediates transcriptional repression of prodifferentiation genes in both normal and neoplastic stem cells. An oncogenic role of EZH2 as a transcriptional silencer is well established; however, additional functions of EZH2 are incompletely understood. Here, we show that EZH2 binds to and [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la protéine SATB1, en l'absence de l'expression du gène p16, pour favoriser la transformation cancéreuse

SATB1 collaborates with loss of p16 in cellular transformation

Agrelo, R. ; Kishimoto, H. ; Novatchkova, M. ; Peraza, V. ; Paolino, M. ; Souabni, A. ; Wutz, A.

Tumor progression is associated with invasiveness and metastatic potential. The special AT-rich binding protein 1 (SATB1) has been identified as a key factor in the progression of breast cancer cells to a malignant phenotype and is associated with progression of human tumors. In normal development, SATB1 coordinates gene expression of progenitor cells by functioning as a genome organizer. In contrast to progenitor and tumor cells, SATB1 expression in nontransformed cells is not compatible with [...]

Menée in vitro, cette étude met en évidence le rôle joué par la voie de signalisation du calcium dans l'induction d'une transition épithélio-mésenchymateuse de cellules de cancer du sein

Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent

Davis, F. M. ; Azimi, I. ; Faville, R. A. ; Peters, A. A. ; Jalink, K. ; Putney Jr, J. W. ; Goodhill, G. J. ; Thompson, E. W. ; Roberts-Thomson, S. J. ; Monteith, G. R.

Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial–mesenchymal transition (EMT). Relatively little is known regarding key signal transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par l'expression des gènes EGF et IGF-1 dans le stroma pour favoriser le processus métastatique d'un cancer du sein triplement négatif

Stromal EGF and IGF1 Together Modulate Plasticity of Disseminated Triple Negative Breast Tumors

Castaño, Zafira ; Marsh, Timothy ; Tadipatri, Ramya ; Kuznetsov, Hanna S ; Al-Shahrour, Fátima ; Paktinat, Mahnaz ; Greene-Colozzi, April ; Nilsson, Björn ; Richardson, Andrea L. ; McAllister, Sandra S

The causes for malignant progression of disseminated tumors and why recurrence rates differ in women with different breast cancer subtypes are unknown. Here, we report novel mechanisms of tumor plasticity that are mandated by microenvironmental factors and demonstrate that recurrence rates are not strictly due to cell intrinsic properties. Specifically, outgrowth of the same population of incipient tumors is accelerated in mice with triple-negative breast cancer (TNBC) relative to those with [...]

Cet article passe en revue les perspectives offertes par un modèle animal, la poule domestique, pour étudier les mécanismes biologiques associés au développement d'un cancer de l'ovaire chez la femme

The hen as a model of ovarian cancer

Johnson, Patricia A. ; Giles, James R.

The domestic laying hen is the only non-human animal that spontaneously develops ovarian cancer with a high prevalence. Hens ovulate prolifically, and this has made the hen intuitively appealing as a model of this disease in light of epidemiological evidence that ovulation rate is highly correlated with the risk of human ovarian cancer. As in women, ovarian cancer in the hen is age-related and it is also grossly and histologically similar to that in humans. In both women and hens, the cancer [...]