Biologie

Aberrations chromosomiques

A partir de 48 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un glioblastome multiforme, cette étude de séquençage des exons identifie des mutations fréquentes d'un gène codant pour l'histone H3.3 et de gènes impliqués dans le remodelage de la chromatine

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
• Nature, sous presse, 2012 (résumé)

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A partir de 48 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un glioblastome multiforme, cette étude de séquençage des exons identifie des mutations fréquentes d'un gène codant pour l'histone H3.3 et de gènes impliqués dans le remodelage de la chromatine

“Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma”

• Schwartzentruber, Jeremy;Korshunov, Andrey;Liu, Xiao-Yang;Jones, David T. W.;Pfaff, Elke;Jacob, Karine;Sturm, Dominik;Fontebasso, Adam M.;Quang, Dong-Anh Khuong;Tonjes, Martje;Hovestadt, Volker;Albrecht, Steffen;Kool, Marcel;Nantel, Andre;Konermann, Carolin;Lindroth, Anders;Jager, Natalie;Rausch, Tobias;Ryzhova, Marina;Korbel, Jan O.;Hielscher, Thomas;Hauser, Peter;Garami, Miklos;Klekner, Almos;Bognar, Laszlo;Ebinger, Martin;Schuhmann, Martin U.;Scheurlen, Wolfram;Pekrun, Arnulf;Fruhwald, Michael C.;Roggendorf, Wolfgang;Kramm, Christoph;Durken, Matthias;Atkinson, Jeffrey;Lepage, Pierre;Montpetit, Alexandre;Zakrzewska, Magdalena;Zakrzewski, Krzystof;Liberski, Pawel P.;Dong, Zhifeng;Siegel, Peter;Kulozik, Andreas E.;Zapatka, Marc;Guha, Abhijit;Malkin, David;Felsberg, Jorg;Reifenberger, Guido;von Deimling, Andreas;Ichimura, Koichi;Collins, V. Peter;Witt, Hendrik;Milde, Till;Witt, Olaf;Zhang, Cindy;Castelo-Branco, Pedro;Lichter, Peter;Faury, Damien;Tabori, Uri;Plass, Christoph;Majewski, Jacek;Pfister, Stefan M.;Jabado, Nada

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX ( α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples ...

Mots clés : Système nerveux central; Biologie (Aberrations chromosomiques)

Menée sur 50 échantillons tumoraux prélevés sur des patients atteints d'un gliome diffus intrinsèque du pont et sur 36 échantillons prélevés sur des patients pédiatriques atteints d'un glioblastome hors du tronc cérébral, cette étude de séquençage évalue la fréquence des mutations somatiques d'un gène codant une histone H3

Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas
• Nature Genetics, sous presse, 2012 (résumé)

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Menée sur 50 échantillons tumoraux prélevés sur des patients atteints d'un gliome diffus intrinsèque du pont et sur 36 échantillons prélevés sur des patients pédiatriques atteints d'un glioblastome hors du tronc cérébral, cette étude de séquençage évalue la fréquence des mutations somatiques d'un gène codant une histone H3

“Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas”

• Gang Wu,;Alberto Broniscer,;Troy A McEachron,;Charles Lu,;Barbara S Paugh,;Jared Becksfort,;Chunxu Qu,;Li Ding,;Robert Huether,;Matthew Parker,;Junyuan Zhang,;Amar Gajjar,;Michael A Dyer,;Charles G Mullighan,;Richard J Gilbertson,;Elaine R Mardis,;Richard K Wilson,;James R Downing,;David W Ellison,;Jinghui Zhang;& Suzanne J Baker;for St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.

Mots clés : Système nerveux central; Biologie (Aberrations chromosomiques)

Menée sur des cellules tumorales circulantes prélevées sur 11 patients atteints d'un mélanome, cette étude analyse les mutations des gènes BRAF et KIT dans ces cellules et révèle leur hétérogénéité clonale

Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level
• British Journal of Cancer, sous presse, 2012 (résumé)

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Menée sur des cellules tumorales circulantes prélevées sur 11 patients atteints d'un mélanome, cette étude analyse les mutations des gènes BRAF et KIT dans ces cellules et révèle leur hétérogénéité clonale

“Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level”

• Sakaizawa, K.;Goto, Y.;Kiniwa, Y.;Uchiyama, A.;Harada, K.;Shimada, S.;Saida, T.;Ferrone, S.;Takata, M.;Uhara, H.;Okuyama, R.

Background: The availability of molecular-targeted therapies for the treatment of melanoma has emphasised the need to identify mutations in target genes such as BRAF and KIT. Circulating tumour cells (CTC) are present in the peripheral blood of a significant proportion of cancer patients. Methods: High molecular weight melanoma-associated antigen (HMW-MAA) was used to isolate melanoma cells from peripheral blood as it is selectively expressed at high levels on melanomas. The HMW-MAA-positive cells were isolated using immunomagnetic beads. After removing CD45+ cells, CTC were identified by staining with MART-1- and gp100-specific antibodies (HMW-MAA+, CD45−, MART-1/gp100+). Single, isolated CTC were then subjected to BRAF and KIT mutational analysis. Results: CTC (HMW-MAA+, CD45−, MART-1/gp100+) were isolated from the blood of 11 patients and BRAF and KIT were sequenced in nine and four patients, respectively. The BRAF sequences identified in the CTC were inconsistent with those ...

Mots clés : Mélanome; Biologie (Aberrations chromosomiques)

Menée sur 10 patients atteints d'un cancer colorectal et traités à l'aide d'anticorps anti EGFR, cette étude identifie la présence d'une mutation qui confère une résistance au cetuximab mais n'annihile pas la sensibilité des cellules cancéreuses au panitumumab

Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer
• Nature Medicine, sous presse, 2012 (résumé)

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Menée sur 10 patients atteints d'un cancer colorectal et traités à l'aide d'anticorps anti EGFR, cette étude identifie la présence d'une mutation qui confère une résistance au cetuximab mais n'annihile pas la sensibilité des cellules cancéreuses au panitumumab

“Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer”

• Montagut, Clara;Dalmases, Alba;Bellosillo, Beatriz;Crespo, Marta;Pairet, Silvia;Iglesias, Mar;Salido, Marta;Gallen, Manuel;Marsters, Scot;Tsai, Siao Ping;Minoche, Andre;Somasekar, Seshagiri;Serrano, Sergi;Himmelbauer, Heinz;Bellmunt, Joaquim;Rovira, Ana;Settleman, Jeff;Bosch, Francesc;Albanell, Joan

Antibodies against epidermal growth factor receptor (EGFR)—cetuximab and panitumumab—are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.

Mots clés : Colon-rectum; Biologie (Aberrations chromosomiques)

Cet article passe en revue les travaux récents sur le rôle de l'aneuploïdie dans la transformation cellulaire

Causes and consequences of aneuploidy in cancer
• Nature Reviews Genetics, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle de l'aneuploïdie dans la transformation cellulaire

“Causes and consequences of aneuploidy in cancer”

• Gordon, David J.;Resio, Benjamin;Pellman, David

Genetic instability, which includes both numerical and structural chromosomal abnormalities, is a hallmark of cancer. Whereas the structural chromosome rearrangements have received substantial attention, the role of whole-chromosome aneuploidy in cancer is much less well-understood. Here we review recent progress in understanding the roles of whole-chromosome aneuploidy in cancer, including the mechanistic causes of aneuploidy, the cellular responses to chromosome gains or losses and how cells might adapt to tolerate these usually detrimental alterations. We also explore the role of aneuploidy in cellular transformation and discuss the possibility of developing aneuploidy-specific therapies.

Mots clés : Cancer (général); Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Cet article passe en revue les travaux récents sur le rôle de dysfonctionnements du gène TP53 dans la genèse d'un lymphome

Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies
• Blood, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle de dysfonctionnements du gène TP53 dans la genèse d'un lymphome

“Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies”

• Xu-Monette, Zijun Y.;Medeiros, L. Jeffrey;Li, Yong;Orlowski, Robert Z.;Andreeff, Michael;Bueso-Ramos, Carlos E.;Greiner, Timothy C.;McDonnell, Timothy J.;Young, Ken H.

Mutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers including lymphomas. Tumor suppression by p53 occurs via both transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent ...

Mots clés : Lymphome; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée in vitro et in vivo, cette étude établit un lien entre un processus inflammatoire, associé à une tumorigenèse du côlon, et la méthylation de l'ADN en montrant que la prostaglandine E2 réduit au silence certains gènes suppresseurs de tumeurs

Prostaglandin E2 promotes intestinal tumor growth via DNA methylation
• Nature Medicine, sous presse, 2012 (résumé)

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Menée in vitro et in vivo, cette étude établit un lien entre un processus inflammatoire, associé à une tumorigenèse du côlon, et la méthylation de l'ADN en montrant que la prostaglandine E2 réduit au silence certains gènes suppresseurs de tumeurs

“Prostaglandin E2 promotes intestinal tumor growth via DNA methylation”

• Xia, Dianren;Wang, Dingzhi;Kim, Sun-Hee;Katoh, Hiroshi;DuBois, Raymond N.

Although aberrant DNA methylation is considered to be one of the key ways by which tumor-suppressor and DNA-repair genes are silenced during tumor initiation and progression, the mechanisms underlying DNA methylation alterations in cancer remain unclear. Here we show that prostaglandin E2 (PGE2) silences certain tumor-suppressor and DNA-repair genes through DNA methylation to promote tumor growth. These findings uncover a previously unrecognized role for PGE2 in the promotion of tumor progression.

Mots clés : Colon-rectum; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur des modèles murins de cancer intestinal, cette étude met en évidence un mécanisme épigénétique de réduction au silence du gène Apc, un suppresseur de tumeurs

Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms
• Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)

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Menée sur des modèles murins de cancer intestinal, cette étude met en évidence un mécanisme épigénétique de réduction au silence du gène Apc, un suppresseur de tumeurs

“Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms”

• Amos-Landgraf, James M.;Irving, Amy A.;Hartman, Cory;Hunter, Anthony;Laube, Brianna;Chen, Xiaodi;Clipson, Linda;Newton, Michael A.;Dove, William F.

Studies of tumors from human familial adenomatous polyposis, sporadic colon cancer, and mouse and rat models of intestinal cancer indicate that the majority of early adenomas develop through loss of normal function of the Adenomatous polyposis coli (APC) gene. In murine models of familial adenomatous polyposis, specifically the multiple intestinal neoplasia mouse (Min) and the polyposis in the rat colon (Pirc) rat, most adenomas have lost their WT copy of the Apc gene through loss of heterozygosity by homologous somatic recombination. We report that large colonic adenomas in the Pirc rat have no detectable copy number losses or gains in genomic material and that most tumors lose heterozygosity only on the short arm of chromosome 18. Examination of early mouse and rat tumors indicates that a substantial subset of tumors shows maintenance of heterozygosity of Apc in genomic DNA, apparently violating Knudson's two-hit hypothesis. Sequencing of the Apc gene in a sampling of rat tumors ...

Mots clés : Colon-rectum; Biologie (Oncogènes et suppresseurs de tumeurs)

Cet article passe en revue les travaux récents sur le rôle de longs ARNs non codants dans le cancer

Long non-coding RNAs and cancer: a new frontier of translational research?
• Oncogene, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle de longs ARNs non codants dans le cancer

“Long non-coding RNAs and cancer: a new frontier of translational research?”

• Spizzo, R.;Almeida, M. I.;Colombatti, A.;Calin, G. A.

Tiling array and novel sequencing technologies have made available the transcription profile of the entire human genome. However, the extent of transcription and the function of genetic elements that occur outside of protein-coding genes, particularly those involved in disease, are still a matter of debate. In this review, we focus on long non-coding RNAs (lncRNAs) that are involved in cancer. We define lncRNAs and present a cancer-oriented list of lncRNAs, list some tools (for example, public databases) that classify lncRNAs or that scan genome spans of interest to find whether known lncRNAs reside there, and describe some of the functions of lncRNAs and the possible genetic mechanisms that underlie lncRNA expression changes in cancer, as well as current and potential future applications of lncRNA research in the treatment of cancer.

Mots clés : Cancer (général); Biologie (Oncogènes et suppresseurs de tumeurs)

Progression et métastases

Menée in vivo et sur 1 532 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer invasif du sein, cette étude identifie un mécanisme par lequel la voie de signalisation PI3K/Akt régule l'activation du facteur de transcription Twist1 et favorise le processus métastatique

Akt/PKB-mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-talk Between PI3K/Akt and TGFβ Signaling Axes
• Cancer Discovery, sous presse, 2012 (résumé)

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Menée in vivo et sur 1 532 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer invasif du sein, cette étude identifie un mécanisme par lequel la voie de signalisation PI3K/Akt régule l'activation du facteur de transcription Twist1 et favorise le processus métastatique

“Akt/PKB-mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-talk Between PI3K/Akt and TGFβ Signaling Axes”

• Xue, Gongda;Restuccia, David F.;Lan, Qiang;Hynx, Debby;Dirnhofer, Stephan;Hess, Daniel;Rüegg, Curzio;Hemmings, Brian A.

Metastatic breast tumor cells display an epithelial-mesenchymal transition (EMT) that increases cell motility, invasion and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here we show that Twist1 is ubiquitously phosphorylated in 90% of 1532 invasive human breast tumors. Akt-mediated Twist1 phosphorylation promotes EMT and breast cancer metastasis by modulating its transcriptional target TGFβ2, leading to enhanced TGFβ receptor signaling, that in turn maintains hyperactive PI3K/Akt signaling. Preventing phosphorylation of Twist1, as well as depletion of TGFβ2, significantly impaired the metastatic potential of cancer cells in vivo, indicating a key role of phosphorylated Twist1 in mediating cross-talk between the PI3K/Akt and TGFβ/Smad signaling axes that supports metastatic tumor development. Our results describe a novel signaling event ...

Mots clés : Sein; Biologie (Progression et métastases)

Menée sur un modèle murin de cancer du sein, cette étude met en évidence l'existence précoce d'une sous-population de cellules tumorales dotées d'un potentiel métastatique

Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers
• Breast Cancer Research, Vol. 14 (1), pp. R18, 2012 (article en libre accès)

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Menée sur un modèle murin de cancer du sein, cette étude met en évidence l'existence précoce d'une sous-population de cellules tumorales dotées d'un potentiel métastatique

“Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers”

• Weng, Desheng;Penzner, Jeffrey;Song, Baizheng;Koido, Shigeo;Calderwood, Stuart;Gong, Jianlin

INTRODUCTION:It is still uncertain whether metastasis is predominantly an early or late event in tumor progression. The detection of early metastases and cells responsible for the dissemination may therefore have significant clinical implications.METHODS:Lung dissemination and/or metastasis were investigated in mice carrying the polyomavirus middle-T oncogene (PyMT) during different stages of mammary tumorigenesis using the colony forming assay. Immunocytochemical or immunohistochemical staining was used to identify subpopulations of cells responsible for lung dissemination and metastasis. Histological examination was used to show primary and metastatic tumors. The tumor-initiating and metastatic capacity of cells expressing stem cell markers was assessed in syngeneic wild-type (WT) mice whose mammary fat pads were injected with these cells.RESULTS:Metastatic mammary epithelial cells were detected in the lungs of mice carrying the PyMT oncogene (MMT mice). These cells were observed ...

Mots clés : Sein; Biologie (Progression et métastases)

Menée sur deux lignées cellulaires de cancer du sein, cette étude met en évidence le rôle de la leptine, une cytokine associée à l'obésité, dans la régulation des interactions entre une tumeur et le stroma favorisant la croissance tumorale

Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells
• Cancer Research, sous presse, 2012 (résumé)

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Menée sur deux lignées cellulaires de cancer du sein, cette étude met en évidence le rôle de la leptine, une cytokine associée à l'obésité, dans la régulation des interactions entre une tumeur et le stroma favorisant la croissance tumorale

“Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells”

• Barone, Ines;Catalano, Stefania;Gelsomino, Luca;Marsico, Stefania;Giordano, Cinzia;Panza, Salvatore;Bonofiglio, Daniela;Bossi, Gianluca;Covington, Kyle R;Fuqua, Suzanne;Ando, Sebastiano

Obesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumor-promoting activity of cancer-associated fibroblasts (CAFs) in both wild-type (WT) and K303R mutant ERα-expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R ERα hyperactive receptor than wild-type ERα-expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R ERα compared to wild-type ERα, correlating with leptin effects on cell growth, motility and invasiveness in mutant cells. EGF and other factors secreted by K303R ERα cells stimulated CAF proliferation, migration, and subsequent leptin secretion. ...

Mots clés : Sein; Biologie (Progression et métastases)

Menée in vitro et sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude identifie un mécanisme impliquant le récepteur des androgènes et l'enzyme PTP1B dans la croissance tumorale

PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer
• Cancer Research, sous presse, 2012 (résumé)

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Menée in vitro et sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude identifie un mécanisme impliquant le récepteur des androgènes et l'enzyme PTP1B dans la croissance tumorale

“PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer”

• Lessard, Laurent;Labbe, David P.;Deblois, Genevieve;Begin, Louis R.;Hardy, Serge;Mes-Masson, Anne-Marie;Saad, Fred;Trotman, Lloyd C.;Giguere, Vincent;Tremblay, Michel L.

The androgen receptor (AR)-signaling axis plays a key role in the pathogenesis of prostate cancer. In this study, we found that the protein tyrosine phosphatase PTP1B, a well-established regulator of metabolic signaling, was induced after androgen stimulation of AR-expressing prostate cancer cells. PTP1B induction by androgen occurred at the mRNA and protein levels to increase PTP1B activity. High-resolution chromosome mapping revealed AR recruitment to two response elements within the first intron of the PTP1B encoding gene PTPN1, correlating with an AR-mediated increase in RNA polymerase II recruitment to the PTPN1 transcriptional start site. We found that PTPN1 and AR genes were co-amplified in metastatic tumors and that PTPN1 amplification was associated with a subset of high-risk primary tumors. Functionally, PTP1B depletion delayed the growth of androgen-dependent human prostate tumors and impaired androgen-induced cell migration and invasion in vitro. However, PTP1B was also ...