Menée à l'aide d'un modèle murin de carcinome hépatocellulaire associé à une infection chronique par le virus de l'hépatite B, cette étude identifie un ensemble de gènes impliqués dans les étapes précoce et tardive de la maladie

Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model

Bard-Chapeau, Emilie A. ; Nguyen, Anh-Tuan ; Rust, Alistair G. ; Sayadi, Ahmed ; Lee, Philip ; Chua, Belinda Q. ; New, Lee-Sun ; de Jong, Johann ; Ward, Jerrold M. ; Chin, Christopher K. Y. ; Chew, Valerie ; Toh, Han Chong ; Abastado, Jean-Pierre ; Benoukraf, Touati ; Soong, Richie ; Bard, Frederic A. ; Dupuy, Adam J. ; Johnson, Randy L. ; Radda, George K. ; Chan, Eric Chun Yong ; Wessels, Lodewyk F. A. ; Adams, David J. ; Jenkins, Nancy A. ; Copeland, Neal G.

The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important [...]

Menée sur deux cohortes de 7 651 et 2 519 patients atteints de cancer, puis à l'aide de drosophiles et de modèles murins, cette étude met en évidence le rôle joué par des mutations du gène CUX1 dans la tumorigenèse

Inactivating CUX1 mutations promote tumorigenesis

Wong, Chi C. ; Martincorena, Inigo ; Rust, Alistair G. ; Rashid, Mamunur ; Alifrangis, Constantine ; Alexandrov, Ludmil B. ; Tiffen, Jessamy C. ; Kober, Christina ; Chronic Myeloid Disorders Working Group of the International Cancer Genome, Consortium ; Green, Anthony R. ; Massie, Charles E. ; Nangalia, Jyoti ; Lempidaki, Stella ; Döhner, Hartmut ; Döhner, Konstanze ; Bray, Sarah J. ; McDermott, Ultan ; Papaemmanuil, Elli ; Campbell, Peter J. ; Adams, David J.

A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ~1–5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of [...]

Menée sur 16 patients atteints d'une maladie autoimmune des tissus conjonctifs (sclérodermie) et d'un cancer, cette étude suggère que des mutations du gène POLR3 sont à l'origine de la sclérodermie pour la plupart des patients présentant des anticorps anti RPC1

Association of the Autoimmune Disease Scleroderma with an Immunologic Response to Cancer

Joseph, Christine G. ; Darrah, Erika ; Shah, Ami A. ; Skora, Andrew D. ; Casciola-Rosen, Livia A. ; Wigley, Fredrick M. ; Boin, Francesco ; Fava, Andrea ; Thoburn, Chris ; Kinde, Isaac ; Jiao, Yuchen ; Papadopoulos, Nickolas ; Kinzler, Kenneth W. ; Vogelstein, Bert ; Rosen, Antony

Autoimmune diseases are thought to be initiated by exposures to foreign antigens that cross-react with endogenous molecules. Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at elevated risk for cancer, we hypothesized that the “foreign” antigens in this autoimmune disease are encoded by somatically mutated genes in [...]

Menée à partir de 104 échantillons tumoraux prélevés sur des patients coréens atteints d'un cancer épidermoïde du poumon, cette étude identifie des anomalies génomiques associées au risque de carcinome épidermoïde du poumon et les compare avec celles présentes dans des échantillons prélévés sur des patients d'Amérique du nord

Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients

Kim, Youngwook ; Hammerman, Peter S. ; Kim, Jaegil ; Yoon, Ji-ae ; Lee, Yoomi ; Sun, Jong-Mu ; Wilkerson, Matthew D. ; Pedamallu, Chandra Sekhar ; Cibulskis, Kristian ; Yoo, Yeong Kyung ; Lawrence, Michael S. ; Stojanov, Petar ; Carter, Scott L. ; McKenna, Aaron ; Stewart, Chip ; Sivachenko, Andrey Y. ; Oh, In-Jae ; Kim, Hong Kwan ; Choi, Yong Soo ; Kim, Kwhanmien ; Shim, Young Mog ; Kim, Kyu-Sik ; Song, Sang-Yun ; Na, Kook-Joo ; Choi, Yoon-La ; Hayes, D. Neil ; Kim, Jhingook ; Cho, Sukki ; Kim, Young-Chul ; Ahn, Jin Seok ; Ahn, Myung-Ju ; Getz, Gad ; Meyerson, Matthew ; Park, Keunchil

Purpose : Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients. Patients and Methods : We performed whole-exome sequencing [...]

Menée sur 110 échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de la cavité buccale, cette étude identifie un ensemble d'anomalies génomiques associées à l'usage de tabac à mâcher ou à chiquer

Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups

India Project Team of the International Cancer Genome, Consortium

Gingivo-buccal oral squamous cell carcinoma (OSCC-GB), an anatomical and clinical subtype of head and neck squamous cell carcinoma (HNSCC), is prevalent in regions where tobacco-chewing is common. Exome sequencing (n=50) and recurrence testing (n=60) reveals that some significantly and frequently altered genes are specific to OSCC-GB (USP9X, MLL4, ARID2, UNC13C and TRPM3), while some others are shared with HNSCC (for example, TP53, FAT1, CASP8, HRAS and NOTCH1). We also find new genes with [...]

Menée à l'aide d'un modèle murin, cette étude confirme l'importance du rôle joué par la kinase BTK dans les leucémies lymphocytaires chroniques

Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL)

Woyach, Jennifer A. ; Bojnik, Engin ; Ruppert, Amy S. ; Stefanovski, Matthew R. ; Goettl, Virginia M. ; Smucker, Kelly A. ; Smith, Lisa L. ; Dubovsky, Jason A. ; Towns, William H. ; MacMurray, Jessica ; Harrington, Bonnie K. ; Davis, Melanie E. ; Gobessi, Stefania ; Laurenti, Luca ; Chang, Betty Y. ; Buggy, Joseph J. ; Efremov, Dimitar G. ; Byrd, John C. ; Johnson, Amy J.

Chronic Lymphocytic Leukemia (CLL) demonstrates variable reactivity of the B cell receptor (BCR) to antigen ligation, but constitutive pathway activation. Bruton's Tyrosine Kinase (BTK) shows constitutive activity in CLL, and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the [...]

Menée sur des bases de données d'expression de gènes dans différents types de gliomes, puis in vitro, cette étude suggère que le gène PID1 joue un rôle de suppresseur de tumeurs

PID1 (NYGGF4), a new growth-inhibitory gene in embryonal brain tumors and gliomas

Erdreich-Epstein, Anat ; Robison, Nathan ; Ren, Xiuhai ; Zhou, Hong ; Xu, Jingying ; Davidson, Tom Belle ; Schur, Mathew ; Gilles, Floyd H ; Ji, Lingyun ; Malvar, Jemily ; Shackleford, Gregory M ; Margol, Ashley ; Krieger, Mark D ; Judkins, Alexander R ; Jones, David TW ; Pfister, Stefan M ; Kool, Marcel ; Sposto, Richard ; Asgharzadeh, Shahab

Purpose: We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was first identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells. Experimental Design: Quantitative RT-PCR, microarrays and cell culture Results: Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (Groups 3 and 4, and anaplastic [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en contrôlant notamment l'apoptose, le gène Ehd3 joue un rôle de suppresseur de tumeurs dans les gliomes

Ehd3, a regulator of vesicular trafficking, is silenced in gliomas and functions as a tumor suppressor by controlling cell cycle arrest and apoptosis

Chukkapalli, Sahiti ; Amessou, Mohamed ; Dekhil, Hafedh ; Dilly, Ashok Kumar ; Liu, Qiang ; Bandyopadhyay, Sudeshna ; Thomas, Ron Dan ; Bejna, Alex ; Batist, Gerald ; Kandouz, Mustapha

EHD3 (Eps15 homology (EH) domain containing protein 3), is a protein that resides in tubular and vesicular membrane structures, and participates in endocytic recycling, although all its functions are unknown. Since Ehd3 is most abundantly expressed in brain tissues, we examined its role in brain cancer progression. Using immunohistochemistry, we report loss of EHD3 expression in gliomas, including low grade astrocytomas, suggesting that this is an early event in gliomagenesis. Ehd3 expression [...]

Cet article passe en revue les travaux récents sur le rôle de l'autophagie dans la croissance tumorale

Autophagy-Mediated Tumor Promotion

Guo, Jessie Yanxiang ; Xia, Bing ; White, Eileen

Mouse models for cancer are revealing novel cancer-promoting roles for autophagy. Autophagy promotes tumor growth by suppressing the p53 response, maintaining mitochondrial function, sustaining metabolic homeostasis and survival in stress, and preventing diversion of tumor progression to benign oncocytomas.

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, dans le microenvironnement, des cellules myéloïdes dérivées de la moelle osseuse et surexprimant CD13 favorisent l'angiogenèse, la croissance tumorale et le processus métastatique

CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis

Dondossola, Eleonora ; Rangel, Roberto ; Guzman-Rojas, Liliana ; Barbu, Elena M. ; Hosoya, Hitomi ; St. John, Lisa S. ; Molldrem, Jeffrey J. ; Corti, Angelo ; Sidman, Richard L. ; Arap, Wadih ; Pasqualini, Renata

Angiogenesis is fundamental to tumorigenesis and an attractive target for therapeutic intervention against cancer. We have recently demonstrated that CD13 (aminopeptidase N) expressed by nonmalignant host cells of unspecified types regulate tumor blood vessel development. Here, we compare CD13 wild-type and null bone marrow-transplanted tumor-bearing mice to show that host CD13+ bone marrow-derived cells promote cancer progression via their effect on angiogenesis. Furthermore, we have [...]

Menée in vitro et in vivo, ainsi qu'à partir de bases de données d'expression de gènes dans des échantillons tumoraux humains, cette étude met en évidence des mécanismes par lesquels le gène Hmga2 favorise la progression d'un cancer du poumon non à petites cellules

HMGA2 functions as a competing endogenous RNA to promote lung cancer progression

Kumar, Madhu S. ; Armenteros-Monterroso, Elena ; East, Philip ; Chakravorty, Probir ; Matthews, Nik ; Winslow, Monte M. ; Downward, Julian

Non-small-cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide. As the majority of patients present with invasive, metastatic disease, it is vital to understand the basis for lung cancer progression. Hmga2 is highly expressed in metastatic lung adenocarcinoma, in which it contributes to cancer progression and metastasis. Here we show that Hmga2 promotes lung cancer progression in mouse and human cells by operating as a competing endogenous RNA (ceRNA) for the [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via la régulation du niveau d'expression d'un récepteur pro-apoptotique (P2X7), le micro-ARN miR-150 favorise la prolifération des cellules de cancer du sein

miR-150 Promotes Human Breast Cancer Growth and Malignant Behavior by Targeting the Pro-Apoptotic Purinergic P2X7Receptor

Huang, Songyin ; Chen, Yongsong ; Wu, Wei ; Ouyang, Nengyong ; Chen, Jianing ; Li, Hongyu ; Liu, Xiaoqiang ; Su, Fengxi ; Lin, Ling ; Yao, Yandan

The P2X7 receptor regulates cell growth through mediation of apoptosis. Low level expression of P2X7 has been linked to cancer development because tumor cells harboring a defective P2X7 mechanism can escape P2X7 pro-apoptotic control. microRNAs (miRNAs) function as negative regulators of post-transcriptional gene expression, playing major roles in cellular differentiation, proliferation, and metastasis. In this study, we found that miR-150 was over-expressed in breast cancer cell lines and [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, en dérégulant l'expression de LCN2, l'inactivation du gène HIC1 favorise le développement d'un cancer du sein triplement négatif

HIC1 silencing in triple-negative breast cancer drives progression through misregulation of LCN2

Cheng, Guangcun ; Sun, Xueqing ; Wang, Jinglong ; Xiao, Gang ; Wang, Xiuming ; Fan, Xuemei ; Zu, Lidong ; Hao, Mingang ; Qu, Qing ; Mao, Yan ; Xue, Yunjing ; Wang, Jianhua

The tumor suppressor gene HIC1 is frequently deleted or epigenetically silenced in human cancer, where its restoration may improve cancer prognosis. Here we report results illuminating how HIC1 silencing alters effect or signals in triple-negative breast cancer (TNBC) which are crucial for its pathogenesis. HIC1 expression was silenced only in TNBC compared to other molecular subtypes of breast cancer. Restoring HIC1 expression in TNBC cells reduced cell migration, invasion and metastasis, [...]