A partir de données du projet "The Cancer Genome Atlas" portant sur 9 types de cancer, cette étude identifie un ensemble d'anomalies génomiques et de processus mutationnels impliqués dans l'évolution des tumeurs

Clonal status of actionable driver events and the timing of mutational processes in cancer evolution

McGranahan, Nicholas ; Favero, Francesco ; de Bruin, Elza C. ; Birkbak, Nicolai Juul ; Szallasi, Zoltan ; Swanton, Charles

Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, lorsqu'ils sont mutés, les gènes TET2 et FLT3 coopèrent pour induire le développement d'une leucémie myéloïde aiguë

Mutational Cooperativity Linked to Combinatorial Epigenetic Gain of Function in Acute Myeloid Leukemia

Shih, Alan H ; Jiang, Yanwen ; Meydan, Cem ; Shank, Kaitlyn ; Pandey, Suveg ; Barreyro, Laura ; Antony-Debre, Ileana ; Viale, Agnes ; Socci, Nicholas ; Sun, Yongming ; Robertson, Alexander ; Cavatore, Magali ; de Stanchina, Elisa ; Hricik, Todd ; Rapaport, Franck ; Woods, Brittany ; Wei, Chen ; Hatlen, Megan ; Baljevic, Muhamed ; Nimer, Stephen D ; Tallman, Martin ; Paietta, Elisabeth ; Cimmino, Luisa ; Aifantis, Iannis ; Steidl, Ulrich ; Mason, Chris ; Melnick, Ari ; Levine, Ross L

Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2−/−;Flt3ITD progenitors (LSK CD48+CD150−) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3ITD mutations and Tet2 loss cooperatively remodeled DNA [...]

Menée sur des modèles murins à l'aide du système de transfert de gènes "Sleeping Beauty", cette étude identifie un ensemble de gènes impliqués dans le développement d'un mélanome présentant la mutation V600E du gène BRAF

Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma

Mann, Michael B. ; Black, Michael A. ; Jones, Devin J. ; Ward, Jerrold M. ; Yew, Christopher Chin Kuan ; Newberg, Justin Y. ; Dupuy, Adam J. ; Rust, Alistair G. ; Bosenberg, Marcus W. ; McMahon, Martin ; Print, Cristin G. ; Copeland, Neal G. ; Jenkins, Nancy A.

Although nearly half of human melanomas harbor oncogenic BRAFV600E mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in BrafV600E mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more [...]

A partir de données issues du projet "The Cancer Genome Atlas" et d'une cohorte japonaise, cette étude identifie un ensemble d'anomalies génomiques impliquées dans l'évolution des gliomes de grade II et III

Mutational landscape and clonal architecture in grade II and III gliomas

Suzuki, Hiromichi ; Aoki, Kosuke ; Chiba, Kenichi ; Sato, Yusuke ; Shiozawa, Yusuke ; Shiraishi, Yuichi ; Shimamura, Teppei ; Niida, Atsushi ; Motomura, Kazuya ; Ohka, Fumiharu ; Yamamoto, Takashi ; Tanahashi, Kuniaki ; Ranjit, Melissa ; Wakabayashi, Toshihiko ; Yoshizato, Tetsuichi ; Kataoka, Keisuke ; Yoshida, Kenichi ; Nagata, Yasunobu ; Sato-Otsubo, Aiko ; Tanaka, Hiroko ; Sanada, Masashi ; Kondo, Yutaka ; Nakamura, Hideo ; Mizoguchi, Masahiro ; Abe, Tatsuya ; Muragaki, Yoshihiro ; Watanabe, Reiko ; Ito, Ichiro ; Miyano, Satoru ; Natsume, Atsushi ; Ogawa, Seishi

Grade II and III gliomas are generally slowly progressing brain cancers, many of which eventually transform into more aggressive tumors. Despite recent findings of frequent mutations in IDH1 and other genes, knowledge about their pathogenesis is still incomplete. Here, combining two large sets of high-throughput sequencing data, we delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes. Grade II and III gliomas [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en inhibant l'apoptose, l'enzyme Sirt7 favorise le développement d'une tumeur gastrique

Sirt7 promotes gastric cancer growth and inhibits apoptosis by epigenetically inhibiting miR-34a

Zhang, Shun ; Chen, Ping ; Huang, Zuoan ; Hu, Xiaorong ; Chen, Mengting ; Hu, Shanshan ; Hu, Yixin ; Cai, Ting

Gastric cancer is the fourth most common cancer worldwide, with a low 5-year survival rate. Epigenetic modification plays pivotal roles in gastric cancer development. However, the role of histone-modifying enzymes in gastric cancer remains largely unknown. Here we report that Sirt7, a NAD+-dependent class III histone deacetylase, is over-expressed in human gastric cancer tissues. Sirt7 level is significantly correlated with disease stage, metastasis, and survival. Knockdown of Sirt7 in gastric [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en favorisant la traduction de certains ARNs messagers, la protéine Stat1 exerce une fonction de suppresseur de tumeurs et, à la fois, favorise la résistance des cellules cancéreuses à des inhibiteurs de PI3K ou mTOR

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Wang, Shuo ; Patsis, Christos ; Koromilas, Antonis E.

The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27Kip1 and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en activant la signalisation Wnt, la protéine TGIF favorise le développement d'une tumeur mammaire

TGIF Governs a Feed-Forward Network that Empowers Wnt Signaling to Drive Mammary Tumorigenesis

Zhang, Ming-Zhu ; Ferrigno, Olivier ; Wang, Zhe ; Ohnishi, Mutsuko ; Prunier, Céline ; Levy, Laurence ; Razzaque, Mohammed ; Horne, Williams C ; Romero, Damian ; Tzivion, Guri ; Colland, Frédéric ; Baron, Roland ; Atfi, Azeddine

Many types of human cancers having hyperactivated Wnt signaling display no causative alterations in known effectors of this pathway. Here, we report a function of TGIF in Wnt signaling. TGIF associates with and diverts Axin1 and Axin2 from the

Cet article présente un ensemble de ressources pour assurer la qualité des lignées cellulaires

A resource for cell line authentication, annotation and quality control

Yu, Mamie ; Selvaraj, Suresh K. ; Liang-Chu, May M. Y. ; Aghajani, Sahar ; Busse, Matthew ; Yuan, Jean ; Lee, Genee ; Peale, Franklin ; Klijn, Christiaan ; Bourgon, Richard ; Kaminker, Joshua S. ; Neve, Richard M.

Cell line misidentification, contamination and poor annotation affect scientific reproducibility. Here we outline simple measures to detect or avoid cross-contamination, present a framework for cell line annotation linked to short tandem repeat and single nucleotide polymorphism profiles, and provide a catalogue of synonymous cell lines. This resource will enable our community to eradicate the use of misidentified lines and generate credible cell-based data.

A partir de cellules prélevées sur un patient atteint d'un syndrome de Li-Fraumeni, cet article analyse le rôle d'un gène p53 muté dans le développement d'un ostéosarcome et démontre la faisabilité d'étudier les cancers d'origine familiale grâce à des cellules souches pluripotentes induites

Modeling Familial Cancer with Induced Pluripotent Stem Cells

Lee, Dung-Fang ; Su, Jie ; Kim, Huen Suk ; Chang, Betty ; Papatsenko, Dmitri ; Zhao, Ruiying ; Yuan, Ye ; Gingold, Julian ; Xia, Weiya ; Darr, Henia ; Mirzayans, Razmik ; Hung, Mien-Chie ; Schaniel, Christoph ; Lemischka, Ihor R

In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in [...]