Cet article passe en revue les travaux récents sur le rôle joué par des réarrangements génomiques complexes, notamment le phénomène de chromothripsis, dans le développement et la progression d'un cancer

Prevalence and clinical implications of chromothripsis in cancer genomes

Kloosterman, Wigard P. ; Koster, Jan ; Molenaar, Jan J.

Purpose of review: A variety of mutational mechanisms shape the landscape of somatic mutations in cancer genomes. Although the contribution of single nucleotide mutations is well studied, getting a hold of structural genomic rearrangements is more difficult due to their complexity and diversity in sizes and classes. Here, we discuss the incidence of complex genomic rearrangements and their impact on cancer development and progression. Recent findings: Catastrophic genome rearrangements have [...]

Menée in vitro, cette étude montre que des cellules sénescentes présentent des anomalies de méthylation de l'ADN semblables aux anomalies observées dans des cellules cancéreuses

Senescent cells harbour features of the cancer epigenome

Cruickshanks, Hazel A. ; McBryan, Tony ; Nelson, David M. ; VanderKraats, Nathan D. ; Shah, Parisha P. ; van Tuyn, John ; Singh Rai, Taranjit ; Brock, Claire ; Donahue, Greg ; Dunican, Donncha S. ; Drotar, Mark E. ; Meehan, Richard R. ; Edwards, John R. ; Berger, Shelley L. ; Adams, Peter D.

Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence is a tumour suppressor process that imposes a limit on the proliferative potential of normal cells that all cancer cells must bypass. Here we show by whole-genome single-nucleotide bisulfite sequencing that replicative senescent human cells exhibit widespread DNA hypomethylation and focal hypermethylation. Hypomethylation occurs preferentially at gene-poor, [...]

A partir d'échantillons prélevés sur des patients atteints d'une leucémie lymphocytaire chronique, cette étude analyse les conséquences fonctionnelles de mutations du gène NOTCH1

Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia

Arruga, F. ; Gizdic, B. ; Serra, S. ; Vaisitti, T. ; Ciardullo, C. ; Coscia, M. ; Laurenti, L. ; D'Arena, G. ; Jaksic, O. ; Inghirami, G. ; Rossi, D. ; Gaidano, G. ; Deaglio, S.

The purpose of this study was to compare the expression and function of NOTCH1 in chronic lymphocytic leukemia (CLL) patients harboring a wild-type (WT) or mutated NOTCH1 gene. NOTCH1 mRNA and surface protein expression levels were independent of the NOTCH1 gene mutational status, consistent with the requirement for NOTCH1 signaling in this leukemia. However, compared with NOTCH1-WT CLL, mutated cases displayed biochemical and transcriptional evidence of an intense activation of the NOTCH1 [...]

Menée sur des échantillons tumoraux prélevés (avant et après traitement à l'aide d'une combinaison dabrafenib-trametinib) sur 5 patients atteints d'un mélanome métastatique présentant la mutation V600E du gène BRAF, cette étude identifie notamment une nouvelle mutation activant l'expression du gène MEK2 en association avec la résistance thérapeutique

MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition

Wagle, Nikhil ; Van Allen, Eliezer M. ; Treacy, Daniel J. ; Frederick, Dennie T. ; Cooper, Zachary A. ; Taylor-Weiner, Amaro ; Rosenberg, Mara ; Goetz, Eva M. ; Sullivan, Ryan J. ; Farlow, Deborah N. ; Friedrich, Dennis C. ; Anderka, Kristin ; Perrin, Danielle ; Johannessen, Cory M. ; McKenna, Aaron ; Cibulskis, Kristian ; Kryukov, Gregory ; Hodis, Eran ; Lawrence, Donald P. ; Fisher, Sheila ; Getz, Gad ; Gabriel, Stacey B. ; Carter, Scott L. ; Flaherty, Keith T. ; Wargo, Jennifer A. ; Garraway, Levi A.

Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired [...]

Menée sur des échantillons tumoraux prélevés sur 45 patients atteints d'un mélanome métastatique présentant la mutation V600E du gène BRAF et ayant été traités à l'aide de vémurafenib ou dabrafenib, cette étude met en évidence un ensemble d'anomalies dans des gènes associés à la résistance aux inhibiteurs de RAF

The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma

Van Allen, Eliezer M. ; Wagle, Nikhil ; Sucker, Antje ; Treacy, Daniel J. ; Johannessen, Cory M. ; Goetz, Eva M. ; Place, Chelsea S. ; Taylor-Weiner, Amaro ; Whittaker, Steven ; Kryukov, Gregory V. ; Hodis, Eran ; Rosenberg, Mara ; McKenna, Aaron ; Cibulskis, Kristian ; Farlow, Deborah ; Zimmer, Lisa ; Hillen, Uwe ; Gutzmer, Ralf ; Goldinger, Simone M. ; Ugurel, Selma ; Gogas, Helen J. ; Egberts, Friederike ; Berking, Carola ; Trefzer, Uwe ; Loquai, Carmen ; Weide, Benjamin ; Hassel, Jessica C. ; Gabriel, Stacey B. ; Carter, Scott L. ; Getz, Gad ; Garraway, Levi A. ; Schadendorf, Dirk

Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance [...]

Menée sur des échantillons tumoraux prélevés sur 838 patients atteints d'un cancer colorectal et 1 765 patients atteints d'un cancer du poumon non à petites cellules, cette étude analyse les différences dans les profils de mutations du gène KRAS entre les deux types de cancer

KRAS mutations in non-small-cell lung cancer and colorectal cancer: implications for EGFR-targeted therapies

Maus, M. K. H. ; Grimminger, P. P. ; Mack, P. C. ; Astrow, S. H. ; Stephens, C. ; Zeger, G. ; Hsiang, J. ; Brabender, J. ; Friedrich, M. ; Alakus, H. ; Hölscher, A. H. ; P.Lara, ; Danenberg, K. D. ; Lenz, H. J. ; Gandara, D. R.

Background : KRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wild-type (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur 123 patientes atteintes d'un cancer du sein, cette étude met en évidence des mécanismes par lesquels des anomalies du nombre de copies de gènes et de méthylation de l'ADN induisent une dérégulation de l'expression d'un ensemble de micro-ARNs

Individual and combined effects of DNA methylation and copy number alterations on miRNA expression in breast tumors

Aure, Miriam ; Leivonen, Suvi-Katri ; Fleischer, Thomas ; Zhu, Qian ; Overgaard, Jens ; Alsner, Jan ; Tramm, Trine ; Louhimo, Riku ; Alnaes, Grethe ; Perälä, Merja ; BUSATO, Florence ; Touleimat, Nizar ; Tost, Jörg ; Borresen-Dale, Anne-Lise ; Hautaniemi, Sampsa ; Troyanskaya, Olga ; Lingjaerde, Ole ; Sahlberg, Kristine ; Kristensen, Vessela

BACKGROUND:The global effect of copy number and epigenetic alterations on miRNA expression in cancer is poorly understood. In the present study, we integrate genome-wide DNA methylation, copy number and miRNA expression and identify genetic mechanisms underlying miRNA dysregulation in breast cancer. RESULTS:We identify 70 miRNAs whose expression was associated with alterations in copy number or methylation, or both. Among these, five miRNA families are represented. Interestingly, the members of [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, via la signalisation Hippo, des niveaux élevés d'acides biliaires peuvent induire le développement d'un cancer du foie

Bile Acids Activate YAP to Promote Liver Carcinogenesis

Anakk, Sayeepriyadarshini ; Bhosale, Manoj ; Schmidt, Valentina A ; Johnson, Randy L ; Finegold, Milton J ; Moore, David D

Elevated bile acid levels increase hepatocellular carcinoma by unknown mechanisms. Here, we show that mice with a severe defect in bile acid homeostasis due to the loss of the nuclear receptors FXR and SHP have enlarged livers, progenitor cell proliferation, and Yes-associated protein (YAP) activation and develop spontaneous liver tumorigenesis. This phenotype mirrors mice with loss of hippo kinases or overexpression of their downstream target, YAP. Bile acids act as upstream regulators of YAP [...]

Menée à l'aide d'un modèle murin de lymphome, cette étude met en évidence des mécanismes par lesquels la caspase-2 joue un rôle de suppresseur de tumeurs

Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice

Puccini, Joseph ; Shalini, Sonia ; Voss, Anne K. ; Gatei, Magtouf ; Wilson, Claire H. ; Hiwase, Devendra K. ; Lavin, Martin F. ; Dorstyn, Loretta ; Kumar, Sharad

Caspase-2, the most evolutionarily conserved member of the caspase family, has been shown to be involved in apoptosis induced by various stimuli. Our recent work indicates that caspase-2 has putative functions in tumor suppression and protection against cellular stress. As such, the loss of caspase-2 enhances lymphomagenesis in Eµ-Myc transgenic mice, and caspase-2 KO (Casp2−/−) mice show characteristics of premature aging. However, the extent and specificity of caspase-2 function in tumor [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en ciblant le gène Rac1, le micro-ARN miR-320a exerce une fonction de suppresseur de tumeurs dans le cancer colorectal

miR-320a suppresses colorectal cancer progression by targeting Rac1

Zhao, Hongchao ; Dong, Taotao ; Zhou, Houmin ; Wang, Linlin ; Huang, Ao ; Feng, Bo ; Quan, Yingjun ; Jin, Runsen ; Zhang, Wenpeng ; Sun, Jing ; Zhang, Daohai ; Zheng, Minhua

MicroRNAs (miRNAs) have emerged as critical epigenetic regulators involved in cancer progression. miR-320a has been identified to be a novel tumour suppressive miRNA in colorectal cancer (CRC). However, the detailed molecular mechanisms are not fully understood. Here, we reported that miR-320a inversely associated with CRC aggressiveness in both cell lines and clinical specimens. Functional studies demonstrated that miR-320a significantly decreased the capability of cell migration/invasion and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant le gène PTEN, une enzyme de déubiquitylation (USP13) joue un rôle de suppresseur de tumeurs dans le cancer du sein

Deubiquitylation and stabilization of PTEN by USP13

Zhang, Jinsong ; Zhang, Peijing ; Wei, Yongkun ; Piao, Hai-long ; Wang, Wenqi ; Maddika, Subbareddy ; Wang, Min ; Chen, Dahu ; Sun, Yutong ; Hung, Mien-Chie ; Chen, Junjie ; Ma, Li

The tumour suppressor PTEN is frequently lost in human cancers. In addition to gene mutations and deletions, recent studies have revealed the importance of post-translational modifications, such as ubiquitylation, in the regulation of PTEN stability, activity and localization. However, the deubiquitylase that regulates PTEN polyubiquitylation and protein stability remains unknown. Here we screened a total of 30 deubiquitylating enzymes (DUBs) and identified five DUBs that physically associate [...]

Cet article passe en revue les travaux récents sur les mécanismes de régulation des cellules souches cancéreuses par des micro-ARNs

MicroRNAs and cancer stem cells: the sword and the shield

Sun, X. ; Jiao, X. ; Pestell, T. G. ; Fan, C. ; Qin, S. ; Mirabelli, E. ; Ren, H. ; Pestell, R. G.

Emerging chemotherapy drugs and targeted therapies have been widely applied in anticancer treatment and have given oncologists a promising future. Nevertheless, regeneration and recurrence are still huge obstacles on the way to cure cancer. Cancer stem cells (CSCs) are capable of self-renewal, tumor initiation, recurrence, metastasis, therapy resistance, and reside as a subset in many, if not all, cancers. Therefore, therapeutics specifically targeting and killing CSCs are being identified, and [...]

Menée sur 41 échantillons de métastases prélevés à l'autopsie sur 17 patients atteints d'un cancer de la prostate résistant à la castration, cette étude analyse l'expression de kinases susceptibles de faire l'objet d'une intervention thérapeutique, puis met en évidence une similarité des profils d'expression entre les métastases de chaque patient ainsi qu'une hétérogénéité d'un patient à l'autre

Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets

Drake, Justin M. ; Graham, Nicholas A. ; Lee, John K. ; Stoyanova, Tanya ; Faltermeier, Claire M. ; Sud, Sudha ; Titz, Bjorn ; Huang, Jiaoti ; Pienta, Kenneth J. ; Graeber, Thomas G. ; Witte, Owen N.

In prostate cancer, multiple metastases from the same patient share similar copy number, mutational status, erythroblast transformation specific (ETS) rearrangements, and methylation patterns supporting their clonal origins. Whether actionable targets such as tyrosine kinases are also similarly expressed and activated in anatomically distinct metastatic lesions of the same patient is not known. We evaluated active kinases using phosphotyrosine peptide enrichment and quantitative mass [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en régulant la traduction de l'ARN messager, la kinase CK1ε favorise la prolifération de cellules de cancer du sein

Casein Kinase 1ε promotes cell proliferation by regulating mRNA translation

Shin, Sejeong ; Wolgamott, Laura ; Roux, Philippe P ; Yoon, Sang-Oh

Deregulation of translation initiation factors contributes to many pathogenic conditions including cancer. Here we report the definition of a novel regulatory pathway for translational initiation with possible therapeutic import in cancer. Specifically, we found that casein kinase 1 ε (CK1ε) is highly expressed in breast tumors and plays a critical role in cancer cell proliferation by controlling mRNA translation. Eukaryotic translation initiation factor eIF4E, an essential component of the [...]

Menée sur des modèles murins, cette étude met en évidence les effets de la température ambiante sur les processus d'immunité antitumorale

Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature

Kokolus, Kathleen M. ; Capitano, Maegan L. ; Lee, Chen-Ting ; Eng, Jason W.-L. ; Waight, Jeremy D. ; Hylander, Bonnie L. ; Sexton, Sandra ; Hong, Chi-Chen ; Gordon, Christopher J. ; Abrams, Scott I. ; Repasky, Elizabeth A.

We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20–26 °C; however, these subthermoneutral temperatures cause mild chronic cold stress, activating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30–31 °C), we observe a striking reduction in [...]

Cet article passe en revue les perspectives offertes par les travaux sur l'évolution de populations microbiennes pour la compréhension des effets d'une hétérogénéité intratumorale sur la résistance thérapeutique et le processus métastatique

Intra-tumor heterogeneity: lessons from microbial evolution and clinical implications

de Bruin, Elza ; Taylor, Tiffany ; Swanton, Charles

Multiple subclonal populations of tumor cells can coexist within the same tumor. This intra-tumor heterogeneity will have clinical implications and it is therefore important to identify factors that drive or suppress such heterogeneous tumor progression. Evolutionary biology can provide important insights into this process. In particular, experimental evolution studies of microbial populations, which exist as clonal populations that can diversify into multiple subclones, have revealed important [...]