Biologie

Aberrations chromosomiques

Menée sur un modèle murin, cette étude met en évidence le rôle joué par une mutation du gène ALK dans les neuroblastomes surexprimant le gène MYCN

The ALKF1174L Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma
• Cancer cell, Vol. 22 (1), pp. 117-130, 2012 (résumé)

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Menée sur un modèle murin, cette étude met en évidence le rôle joué par une mutation du gène ALK dans les neuroblastomes surexprimant le gène MYCN

“The ALKF1174L Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma”

• Berry, Teeara;Luther, William;Bhatnagar, Namrata;Jamin, Yann;Poon, Evon;Sanda, Takaomi;Pei, Desheng;Sharma, Bandana;Vetharoy, Winston R;Hallsworth, Albert;Ahmad, Zai;Barker, Karen;Moreau, Lisa;Webber, Hannah;Wang, Wenchao;Liu, Qingsong;Perez-Atayde, Antonio;Rodig, Scott;Cheung, Nai-Kong;Raynaud, Florence;Hallberg, Bengt;Robinson, Simon P;Gray, Nathanael S;Pearson, Andrew D J.;Eccles, Suzanne A;Chesler, Louis;George, Rani E

The ALKF1174L mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALKF1174L in the neural crest. Compared to ALKF1174L and MYCN alone, co-expression of these two oncogenes led to the development of neuroblastomas with earlier onset, higher penetrance, and enhanced lethality. ALKF1174L/MYCN tumors exhibited increased MYCN dosage due to ALKF1174L-induced activation of the PI3K/AKT/mTOR and MAPK pathways, coupled with suppression of MYCN pro-apoptotic effects. Combined treatment with the ATP-competitive mTOR inhibitor Torin2 overcame the resistance of ALKF1174L/MYCN tumors to crizotinib. Our findings demonstrate a pathogenic role for ALKF1174L in neuroblastomas overexpressing MYCN and suggest a strategy for improving targeted therapy for ALK-positive neuroblastoma. º A murine model of ALKF1174L/MYCN neuroblastoma is presented º ALK potentiates MYCN-driven ...

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

Ces deux études mettent en évidence le rôle clé joué par la protéine MMS19 dans le métabolisme de l'ADN et le maintien de l'intégrité du génome

MMS19 Assembles Iron-Sulfur Proteins Required for DNA Metabolism and Genomic Integrity
• Science, Vol. 337 (6091), pp. 195-199, 2012 (résumé)

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Ces deux études mettent en évidence le rôle clé joué par la protéine MMS19 dans le métabolisme de l'ADN et le maintien de l'intégrité du génome

“MMS19 Assembles Iron-Sulfur Proteins Required for DNA Metabolism and Genomic Integrity”

• Stehling, Oliver;Vashisht, Ajay A.;Mascarenhas, Judita;Jonsson, Zophonias O.;Sharma, Tanu;Netz, Daili J. A.;Pierik, Antonio J.;Wohlschlegel, James A.;Lill, Roland

Instability of the nuclear genome is a hallmark of cancer and aging. MMS19 protein has been linked to maintenance of genomic integrity, but the molecular basis of this connection is unknown. Here, we identify MMS19 as a member of the cytosolic iron-sulfur protein assembly (CIA) machinery. MMS19 functions as part of the CIA targeting complex that specifically interacts with and facilitates iron-sulfur cluster insertion into apoproteins involved in methionine biosynthesis, DNA replication, DNA repair, and telomere maintenance. MMS19 thus serves as an adapter between early-acting CIA components and a subset of cellular iron-sulfur proteins. The function of MMS19 in the maturation of crucial components of DNA metabolism may explain the sensitivity of MMS19 mutants to DNA damage and the presence of extended telomeres.
MMS19 Links Cytoplasmic Iron-Sulfur Cluster Assembly to DNA Metabolism
• Science, Vol. 337 (6091), pp. 243-245, 2012 (résumé)

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Ces deux études mettent en évidence le rôle clé joué par la protéine MMS19 dans le métabolisme de l'ADN et le maintien de l'intégrité du génome

“MMS19 Links Cytoplasmic Iron-Sulfur Cluster Assembly to DNA Metabolism”

• Gari, Kerstin ; León Ortiz, Ana María ; Borel, Valérie ; Flynn, Helen ; Skehel, J. Mark ; Boulton, Simon J.

The function of many DNA metabolism proteins depends on their ability to coordinate an iron-sulfur (Fe-S) cluster. Biogenesis of Fe-S proteins is a multistep process that takes place in mitochondria and the cytoplasm, but how it is linked to nuclear Fe-S proteins is not known. Here, we demonstrate that MMS19 forms a complex with the cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18. Cytoplasmic MMS19 also binds to multiple nuclear Fe-S proteins involved in DNA metabolism. In the absence of MMS19, a failure to transfer Fe-S clusters to target proteins is associated with Fe-S protein instability and preimplantation death of mice in which Mms19 has been knocked out. We propose that MMS19 functions as a platform to facilitate Fe-S cluster transfer to proteins critical for DNA replication and repair.
Fragile Delivery to the Genome
• Science, Vol. 337 (6091), pp. 160-161, 2012 (commentaire)

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Ces deux études mettent en évidence le rôle clé joué par la protéine MMS19 dans le métabolisme de l'ADN et le maintien de l'intégrité du génome

“Fragile Delivery to the Genome”

• Gottschling, Daniel E.

When an important, fragile package needs to be delivered with high assurance, a dependable envoy can ensure that it lands in the right hands. Iron-sulfur (Fe-S) clusters are one such package in the cell. Many proteins, including some that replicate and maintain the nuclear genome, require them. Two papers in this issue—by Gari et al. (1) on page 243 and Stehling et al. (2) on page 195—identify MMS19 as the envoy that delivers Fe-S clusters to enzymes that maintain genome integrity.

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

Oncogènes et suppresseurs de tumeurs

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du micro-ARN 155, une version mutée du gène p53 favorise le processus invasif d'un cancer du sein

Mutant p53 drives invasion in breast tumors through up-regulation of miR-155
• Oncogene, sous presse, 2012 (résumé)

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Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du micro-ARN 155, une version mutée du gène p53 favorise le processus invasif d'un cancer du sein

“Mutant p53 drives invasion in breast tumors through up-regulation of miR-155”

• Neilsen, P. M.;Noll, J. E.;Mattiske, S.;Bracken, C. P.;Gregory, P. A.;Schulz, R. B.;Lim, S. P.;Kumar, R.;Suetani, R. J.;Goodall, G. J.;Callen, D. F.

Loss of p53 function is a critical event during tumorigenesis, with half of all cancers harboring mutations within the TP53 gene. Such events frequently result in the expression of a mutated p53 protein with gain-of-function properties that drive invasion and metastasis. Here, we show that the expression of miR-155 was up-regulated by mutant p53 to drive invasion. The miR-155 host gene was directly repressed by p63, providing the molecular basis for mutant p53 to drive miR-155 expression. Significant overlap was observed between miR-155 targets and the molecular profile of mutant p53-expressing breast tumors in vivo. A search for cancer-related target genes of miR-155 revealed ZNF652, a novel zinc-finger transcriptional repressor. ZNF652 directly repressed key drivers of invasion and metastasis, such as TGFB1, TGFB2, TGFBR2, EGFR, SMAD2 and VIM. Furthermore, silencing of ZNF652 in epithelial cancer cell lines promoted invasion into matrigel. Importantly, loss of ZNF652 expression in ...

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

Menée in vitro et in vivo, cette étude montre que CD36, un récepteur transmembranaire, joue un rôle similaire dans les tissus tumoraux et les tissus de haute densité mammographique

CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues
• Cancer Discovery, sous presse, 2012 (résumé)

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Menée in vitro et in vivo, cette étude montre que CD36, un récepteur transmembranaire, joue un rôle similaire dans les tissus tumoraux et les tissus de haute densité mammographique

“CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues”

• DeFilippis, Rosa Anna;Chang, Hang;Dumont, Nancy;Rabban, Joseph T;Chen, Yunn-Yi;Fontenay, Gerald V.;Berman, Hal K.;Gauthier, Mona L.;Zhao, Jianxin;Hu, Donglei;Marx, James J;Tjoe, Judy A;Ziv, Elad;Febbraio, Maria;Kerlikowske, Karla;Parvin, Bahram;Tlsty, Thea D.

Although high mammographic density (MD) is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high MD share key histological features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high ECM content. We show that CD36, a transmembrane receptor that coordinately modulates multiple pro-tumorigenic phenotypes including adipocyte differentiation, angiogenesis, cell-ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high MD and tumor stroma. Using both in vitro and in vivo assays, we demonstrate that CD36 repression is necessary and sufficient to recapitulate the abovementioned phenotypes observed in high MD and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with ...

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

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel, en activant la voie de signalisation PI3K/AKT, l'expression intratumorale de COX-2 favorise le développement d'un adénocarcinome canalaire du pancréas

Cell Intrinsic Role of Cox-2 in Pancreatic Cancer Development
• Molecular Cancer Therapeutics, sous presse, 2012 (résumé)

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Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel, en activant la voie de signalisation PI3K/AKT, l'expression intratumorale de COX-2 favorise le développement d'un adénocarcinome canalaire du pancréas

“Cell Intrinsic Role of Cox-2 in Pancreatic Cancer Development”

• Hill, Reginald;Li, Yunfeng;Tran, Linh M.;Dry, Sarah;Hargan Calvopina, Joseph;Garcia, Alejandro J;Kim, Christine;Wang, Ying;Donahue, Timothy R.;Herschman, Harvey R.;Wu, Hong

Cyclooxygenase-2 (COX-2) is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of non steroidal anti-inflammatory drugs (NSAIDs) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic vs. microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression, using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 over-expression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 over-expression increases P-AKT levels in the ...

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

Menée à l'aide d'un modèle murin, cette étude montre que la voie de signalisation Blk joue un rôle de suppresseur de tumeurs dans les cellules souches de leucémie myéloïde chronique

The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells
• Nature Genetics, sous presse, 2012 (résumé)

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Menée à l'aide d'un modèle murin, cette étude montre que la voie de signalisation Blk joue un rôle de suppresseur de tumeurs dans les cellules souches de leucémie myéloïde chronique

“The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells”

• Zhang, Haojian;Peng, Cong;Hu, Yiguo;Li, Huawei;Sheng, Zhi;Chen, Yaoyu;Sullivan, Con;Cerny, Jan;Hutchinson, Lloyd;Higgins, Anne;Miron, Patricia;Zhang, Xueqing;Brehm, Michael A.;Li, Dongguang;Green, Michael R.;Li, Shaoguang

A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on the identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL–induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL downregulates the Blk gene (encoding B-lymphoid kinase) through c-Myc in leukemic stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells. Our results show the feasibility of selectively targeting LSCs, an ...

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

Menée sur un modèle murin, cette étude montre qu'une séléno-enzyme, la thiorédoxine réductase de type 1, protège contre l'hépatocarcinogenèse chimiquement induite en contrôlant l'homéostasie redox des cellules

Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis via control of cellular redox homeostasis
• Carcinogenesis, sous presse, 2012 (résumé)

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Menée sur un modèle murin, cette étude montre qu'une séléno-enzyme, la thiorédoxine réductase de type 1, protège contre l'hépatocarcinogenèse chimiquement induite en contrôlant l'homéostasie redox des cellules

“Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis via control of cellular redox homeostasis”

• Carlson, Bradley A;Yoo, Min-Hyuk;Tobe, Ryuta;Mueller, Charles;Naranjo-Suarez, Salvador;Hoffmann, Victoria J;Gladyshev, Vadim N;Hatfield, Dolph

Thioredoxin reductase 1 (TR1) controls the redox state of protein thiols in mammalian cells and has been shown to have roles in both preventing and promoting cancer. To define the role of this selenoenzyme in hepatocellular carcinoma development, we examined tumor incidence in the liver of mice with tissue-specific knockout of mouse TR1 subjected to the liver carcinogen, diethylnitrosamine (DEN). TR1-deficient livers manifested ~90% tumor incidence compared to ~16% in control livers. The TR1-dependent effect was observed independent of sex, and, in control mice, tumorigenesis did not affect the expression of TR1. On the other hand, we observed up-regulation of another selenoenzyme, glutathione peroxidase 2, and components of the glutathione system, including those that generate reduced glutathione. Overall, this study shows that TR1 protects against chemically induced hepatocarcinogenesis via the control of the cellular redox state, whereas its role in promoting this type of cancer is ...

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

Cet article passe en revue les travaux récents sur le rôle d'une enzyme de la biosynthèse des acides gras, l'ATP-citrate lyase, dans les cellules cancéreuses

ATP-Citrate Lyase: A Key Player in Cancer Metabolism
• Cancer Research, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle d'une enzyme de la biosynthèse des acides gras, l'ATP-citrate lyase, dans les cellules cancéreuses

“ATP-Citrate Lyase: A Key Player in Cancer Metabolism”

• Zaidi, Nousheen;Swinnen, Johannes V.;Smans, Karine

ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes the generation of acetyl CoA from citrate. Acetyl CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. Acetyl CoA is also required for acetylation reactions that modify proteins, such as histone acetylation. ACLY is upregulated or activated in several types of cancers, and its inhibition is known to induce proliferation arrest in cancer cells both in vitro and in vivo. The present review highlights current knowledge about the role of ACLY in cancer cells, with special reference to the different pathways that are linked by ACLY. Cancer Res; 72(15); 1–6. ©2012 AACR.

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

Cet article passe en revue les travaux récents sur le rôle du réseau des récepteurs HER à activité tyrosine kinase dans le développement des cancers et dans les mécanismes de résistance thérapeutique

The ERBB network: at last, cancer therapy meets systems biology
• Nature Reviews Cancer, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle du réseau des récepteurs HER à activité tyrosine kinase dans le développement des cancers et dans les mécanismes de résistance thérapeutique

“The ERBB network: at last, cancer therapy meets systems biology”

• Yarden, Yosef;Pines, Gur

Although it is broadly agreed that the improved treatment of patients with cancer will depend on a deeper molecular understanding of the underlying pathogenesis, only a few examples are already available. This Timeline article focuses on the ERBB (also known as HER) network of receptor tyrosine kinases (RTKs), which exemplifies how a constant dialogue between basic research and medical oncology can translate into both a sustained pipeline of novel drugs and ways to overcome acquired treatment resistance in patients. We track the key early discoveries that linked this RTK family to oncogenesis, the course of pioneering clinical research and their merger into a systems-biology framework that is likely to inspire further generations of effective therapeutic strategies.

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

Progression et métastases

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par SOX4, fréquemment surexprimée dans les cancers du sein triplement négatifs, dans l'induction d'une transition épithélio-mésenchymateuse et la progression d'un cancer du sein

SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression
• Cancer Research, sous presse, 2012 (résumé)

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Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par SOX4, fréquemment surexprimée dans les cancers du sein triplement négatifs, dans l'induction d'une transition épithélio-mésenchymateuse et la progression d'un cancer du sein

“SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression”

• Zhang, Jianchao;Liang, Qian;Lei, Yang;Yao, Min;Li, Lili;Gao, Xiaoge;Feng, Jingxin;Zhang, Yu;Gao, Hongwen;Liu, Dong-Xu;Lu, Jun;Huang, Baiqu

Epithelial-mesenchymal transition (EMT) is a developmental program, which is associated with breast cancer progression and metastasis. Here we report that ectopic overexpression of SOX4 in immortalized human mammary epithelial cells is sufficient for acquisition of mesenchymal traits, enhanced cell migration and invasion, along with epithelial stem cell properties that defined by the presence of a CD44high/CD24low cell subpopulation. SOX4 positively regulated expression of known EMT inducers, also activating the TGF-β pathway to contribute to EMT. SOX4 itself was induced by TGF-β in mammary epithelial cells and was required for TGF-β-induced EMT. Murine xenograft experiments showed that SOX4 cooperated with oncogenic Ras to promote tumorigenesis in vivo. Finally, in clinical specimens of human breast cancer, we found that SOX4 was abnormally overexpressed and correlated with the triple-negative breast cancer subtype (ER-/PR-/HER2-). Our findings define an important function for ...

Mots clés : Sein; Biologie (Progression et métastases)

Menée sur un modèle murin, cette étude met en évidence le rôle joué par la protéine Rac1b dans la transition épithélio-mésenchymateuse et la progression d'un adénocarcinome du poumon

Matrix Metalloproteinase Induction of Rac1b, a Key Effector of Lung Cancer Progression
• Science Translational Medicine, Vol. 4 (142), pp. 142ra95, 2012 (résumé)

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Menée sur un modèle murin, cette étude met en évidence le rôle joué par la protéine Rac1b dans la transition épithélio-mésenchymateuse et la progression d'un adénocarcinome du poumon

“Matrix Metalloproteinase Induction of Rac1b, a Key Effector of Lung Cancer Progression”

• Stallings-Mann, Melody L.;Waldmann, Jens;Zhang, Ying;Miller, Erin;Gauthier, Mona L.;Visscher, Daniel W.;Downey, Gregory P.;Radisky, Evette S.;Fields, Alan P.;Radisky, Derek C.

Lung cancer is more deadly than colon, breast, and prostate cancers combined, and treatment improvements have failed to improve prognosis significantly. Here, we identify a critical mediator of lung cancer progression, Rac1b, a tumor-associated protein with cell-transforming properties that are linked to the matrix metalloproteinase (MMP)–induced epithelial-mesenchymal transition (EMT) in lung epithelial cells. We show that expression of mouse Rac1b in lung epithelial cells of transgenic mice stimulated EMT and spontaneous tumor development and that activation of EMT by MMP-induced expression of Rac1b gave rise to lung adenocarcinoma in the transgenic mice through bypassing oncogene-induced senescence. Rac1b is expressed abundantly in stages 1 and 2 of human lung adenocarcinomas and, hence, is an attractive molecular target for the development of new therapies that prevent progression to later-stage lung cancers.
Got a Light? Illuminating Lung Cancer
• Science Translational Medicine, Vol. 4 (142), pp. 142fs22, 2012 (commentaire)

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Menée sur un modèle murin, cette étude met en évidence le rôle joué par la protéine Rac1b dans la transition épithélio-mésenchymateuse et la progression d'un adénocarcinome du poumon

“Got a Light? Illuminating Lung Cancer”

• McAllister, Sandra S.

New mouse models shed light on mechanisms of lung cancer progression and pinpoint Rac1b as a potential therapeutic target (Stallings-Mann et al., this issue).

Mots clés : Poumon; Biologie (Progression et métastases)

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant la signalisation BRAF, la protéine kinase RSK favorise la croissance des cellules de mélanome

RSK regulates activated BRAF signalling to mTORC1 and promotes melanoma growth
• Oncogene, sous presse, 2012 (résumé)

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Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant la signalisation BRAF, la protéine kinase RSK favorise la croissance des cellules de mélanome

“RSK regulates activated BRAF signalling to mTORC1 and promotes melanoma growth”

• Romeo, Y.;Moreau, J.;Zindy, P. J.;Saba-El-Leil, M.;Lavoie, G.;Dandachi, F.;Baptissart, M.;Borden, K. L. B.;Meloche, S.;Roux, P. P.

The Ras/mitogen-activated protein kinase (MAPK) signalling cascade regulates various biological functions, including cell growth, proliferation and survival. As such, this pathway is often deregulated in cancer, including melanomas, which frequently harbour activating mutations in the NRAS and BRAF oncogenes. Hyperactive MAPK signalling is known to promote protein synthesis, but the mechanisms by which this occurs remain poorly understood. Here, we show that expression of oncogenic forms of Ras and Raf promotes the constitutive activation of the mammalian target of rapamycin (mTOR). Using pharmacological inhibitors and RNA interference, we find that the MAPK-activated protein kinase RSK (p90 ribosomal S6 kinase) is partly required for these effects. Using melanoma cell lines carrying activating BRAF mutations, we show that ERK/RSK signalling regulates assembly of the translation initiation complex and polysome formation, as well as the translation of growth-related messenger RNAs ...

Mots clés : Mélanome; Biologie (Progression et métastases)

Ressources et infrastructures (Biologie)

Cet article passe en revue les travaux récents suggérant des interactions entre altérations génétiques et altérations épigénétiques dans les cancers

Cancer Genetics and Epigenetics: Two Sides of the Same Coin?
• Cancer cell, Vol. 22 (1), pp. 9-20, 2012 (résumé)

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Cet article passe en revue les travaux récents suggérant des interactions entre altérations génétiques et altérations épigénétiques dans les cancers

“Cancer Genetics and Epigenetics: Two Sides of the Same Coin?”

• You, Jueng Soo;Jones, Peter A

Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy.

Mots clés : Cancer (général); Biologie (Ressources et infrastructures (Biologie))

A partir de données portant sur plus de 1 800 participants du "Personal Genome Project", cette étude présente un outil appelé "Environment-Trait Evidence" pour faciliter l'usage clinique des données génomiques

A public resource facilitating clinical use of genomes
• Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)

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A partir de données portant sur plus de 1 800 participants du "Personal Genome Project", cette étude présente un outil appelé "Environment-Trait Evidence" pour faciliter l'usage clinique des données génomiques

“A public resource facilitating clinical use of genomes”

• Ball, Madeleine P.;Thakuria, Joseph V.;Zaranek, Alexander Wait;Clegg, Tom;Rosenbaum, Abraham M.;Wu, Xiaodi;Angrist, Misha;Bhak, Jong;Bobe, Jason;Callow, Matthew J.;Cano, Carlos;Chou, Michael F.;Chung, Wendy K.;Douglas, Shawn M.;Estep, Preston W.;Gore, Athurva;Hulick, Peter;Labarga, Alberto;Lee, Je-Hyuk;Lunshof, Jeantine E.;Kim, Byung Chul;Kim, Jong-Il;Li, Zhe;Murray, Michael F.;Nilsen, Geoffrey B.;Peters, Brock A.;Raman, Anugraha M.;Rienhoff, Hugh Y.;Robasky, Kimberly;Wheeler, Matthew T.;Vandewege, Ward;Vorhaus, Daniel B.;Yang, Joyce L.;Yang, Luhan;Aach, John;Ashley, Euan A.;Drmanac, Radoje;Kim, Seong-Jin;Li, Jin Billy;Peshkin, Leonid;Seidman, Christine E.;Seo, Jeong-Sun;Zhang, Kun;Rehm, Heidi L.;Church, George M.

Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board- approved “open consent” process. The contribution of public data and samples facilitates both scientific discovery and standardization of methods. We present our findings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the Genome-Environment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we find numerous literature references implying serious disease. ...