Menée sur 10 patients porteurs du virus de l'hépatite B et atteints d'un carcinome hépatocellulaire présentant des métastases intra-hépatiques, cette étude de séquençage des exons identifie des mutations dans sept gènes, notamment VCAM1 et CDK14, favorisant la croissance et l'infiltration des cellules cancéreuses

Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma

Huang, Jian ; Deng, Qing ; Wang, Qun ; Li, Kun-Yu ; Dai, Ji-Hong ; Li, Niu ; Zhu, Zhi-Dong ; Zhou, Bo ; Liu, Xiao-Yan ; Liu, Rui-Fang ; Fei, Qian-Lan ; Chen, Hui ; Cai, Bing ; Zhou, Boping ; Xiao, Hua-Sheng ; Qin, Lun-Xiu ; Han, Ze-Guang

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and shows a propensity to metastasize and infiltrate adjacent and more distant tissues. HCC is associated with multiple risk factors, including hepatitis B virus (HBV) infection, which is especially prevalent in China. Here, we used exome sequencing to identify somatic mutations in ten HBV-positive individuals with HCC with portal vein tumor thromboses (PVTTs), intrahepatic metastases. Both C:G>A:T and T:A>A:T [...]

Menée sur 223 échantillons tumoraux prélevés sur des patients adultes atteints d'une leucémie lymphoblastique aiguë T, cette étude analyse le spectre des anomalies du gène MLL

Involvement of the MLL gene in adult T-lymphoblastic leukemia

Türkmen, Seval ; Timmermann, Bernd ; Bartels, Gesine ; Gröger, Daniela ; Meyer, Claus ; Schwartz, Stefan ; Haferlach, Claudia ; Rieder, Harald ; Gökbuget, Nicola ; Hoelzer, Dieter ; Marschalek, Rolf ; Burmeister, Thomas

While the MLL “recombinome” is relatively well characterized in B-cell precursor acute lymphoblastic leukemia (BCP ALL), available data for adult acute T-lymphoblastic leukemia (T-ALL) are scarce. We performed fluorescence in situ hybridization (FISH) for an MLL split signal on 223 adult T-ALL samples obtained within the framework of the German Multicenter ALL 07/2003 therapy trial. Three biphenotypic leukemias (T-ALL/AML) were also included in the analysis. Samples showing any alteration by [...]

Menée sur des lignées cellulaires d'adénocarcinome du poumon, cette étude identifie des mutations somatiques oncogéniques du domaine extracellulaire du gène ERBB2, qui code la protéine HER2, et suggère que des thérapies ciblées sur ERBB2 pourraient bénéficier aux patients dont les tumeurs présentent ces mutations

Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2

Greulich, Heidi ; Kaplan, Bethany ; Mertins, Philipp ; Chen, Tzu-Hsiu ; Tanaka, Kumiko E. ; Yun, Cai-Hong ; Zhang, Xiaohong ; Lee, Se-Hoon ; Cho, Jeonghee ; Ambrogio, Lauren ; Liao, Rachel ; Imielinski, Marcin ; Banerji, Shantanu ; Berger, Alice H. ; Lawrence, Michael S. ; Zhang, Jinghui ; Pho, Nam H. ; Walker, Sarah R. ; Winckler, Wendy ; Getz, Gad ; Frank, David ; Hahn, William C. ; Eck, Michael J. ; Mani, D. R. ; Jaffe, Jacob D. ; Carr, Steven A. ; Wong, Kwok-Kin ; Meyerson, Matthew

We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation or by covalent dimerization mediated by [...]

Menée sur des échantillons tumoraux prélevés sur 116 patientes atteintes d'un carcinome canalaire in situ du sein, cette étude identifie des gènes dont le nombre de copies est associé à la capacité de progression vers un carcinome invasif

Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast

Liao, Shaoxi ; Desouki, Mohamed M. ; Gaile, Daniel P. ; Shepherd, Lori ; Nowak, Norma J. ; Conroy, Jeffrey ; Barry, William T. ; Geradts, Joseph

Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease. We microdissected 206 paraffin blocks representing 116 different cases of low-grade ductal carcinoma in situ (DCIS). Fifty-five were pure DCIS (PD) cases without progression to invasive carcinoma. Sixty-one cases had a small invasive component. DNA was extracted from microdissected sections and hybridized to high-density bacterial artificial chromosome arrays. Array comparative genomic hybridization [...]

Menée sur des modèles murins, cette étude met en évidence le rôle joué par Apobec1, une enzyme de la famille des cytidine désaminases, dans le contrôle des modifications épigénétiques conférant une susceptibilité, transmise d'une génération à une autre, à une tumeur testiculaire à cellules germinales

Transgenerational epigenetic effects of the Apobec1 cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

Nelson, Vicki R. ; Heaney, Jason D. ; Tesar, Paul J. ; Davidson, Nicholas O. ; Nadeau, Joseph H.

Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Deadend1 (Dnd1) gene enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by interacting epigenetically with other TGCT modifier genes in previous [...]

Menée sur 76 échantillons tumoraux prélevés sur des patientes atteintes d'un carcinome séreux de l'ovaire, cette étude de séquençage des exons identifie des mutations somatiques dans divers gènes, notamment p53, FBXW7 et PI3KCA

Identification of Molecular Pathway Aberrations in Uterine Serous Carcinoma by Genome-wide Analyses

Kuhn, Elisabetta ; Wu, Ren-Chin ; Guan, Bin ; Wu, Gang ; Zhang, Jinghui ; Wang, Yue ; Song, Lei ; Yuan, Xiguo ; Wei, Lei ; Roden, Richard B.S. ; Kuo, Kuan-Tin ; Nakayama, Kentaro ; Clarke, Blaise ; Shaw, Patricia ; Olvera, Narciso ; Kurman, Robert J. ; Levine, Douglas A. ; Wang, Tian-Li ; Shih, Ie-Ming

Background Uterine cancer is the fourth most common malignancy in women, and uterine serous carcinoma is the most aggressive subtype. However, the molecular pathogenesis of uterine serous carcinoma is largely unknown. We analyzed the genomes of uterine serous carcinoma samples to better understand the molecular genetic characteristics of this cancer. Methods Whole-exome sequencing was performed on 10 uterine serous carcinomas and the matched normal blood or tissue samples. Somatically acquired [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en inhibant la voie de signalisation AKT/mTOR, la protéine ADAMTS9 exerce une fonction de suppresseur de tumeurs dans le cancer gastrique

ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer

Du, W. ; Wang, S. ; Zhou, Q. ; Li, X. ; Chu, J. ; Chang, Z. ; Tao, Q. ; Ng, E. K. O. ; Fang, J. ; Sung, J. J. Y. ; Yu, J.

Using genome-wide promoter methylation analysis, we identified a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9 (ADAMTS9) is methylated in cancer. We aim to clarify its epigenetic inactivation, biological function and clinical implication in gastric cancer. ADAMTS9 was silenced in 6 out of 8 gastric cancer cell lines. The loss of ADAMTS9 expression was regulated by promoter hypermethylation and could be restored by demethylation agent. Ectopic expression of ADAMTS9 in [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la bactérie Helicobacter pylori modifie le profil d'expression des isoformes de la protéine p53

Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses

Wei, Jinxiong ; Noto, Jennifer ; Zaika, Elena ; Romero-Gallo, Judith ; Correa, Pelayo ; El-Rifai, Wael ; Peek, Richard M. ; Zaika, Alexander

The p53 protein plays a central role in the prevention of tumorigenesis. Cellular stresses, such as DNA damage and aberrant oncogene activation, trigger induction of p53 that halts cellular proliferation and allows cells to be repaired. If cellular damage is beyond the capability of the repair mechanisms, p53 induces apoptosis or cell cycle arrest, preventing damaged cells from becoming cancerous. However, emerging evidence suggests that the function of p53 needs to be considered as [...]

Cet article passe en revue l'histoire des travaux sur les oncogènes rétroviraux

Retroviral oncogenes: a historical primer

Vogt, Peter K.

Retroviruses are the original source of oncogenes. The discovery and characterization of these genes was made possible by the introduction of quantitative cell biological and molecular techniques for the study of tumour viruses. Key features of all retroviral oncogenes were first identified in src, the oncogene of Rous sarcoma virus. These include non-involvement in viral replication, coding for a single protein and cellular origin. The MYC, RAS and ERBB oncogenes quickly followed SRC, and [...]

Menée sur des lignées cellulaires de mélanome et des échantillons tumoraux, cette étude met en évidence le rôle joué par la protéine RSK2 dans la transformation néoplasique des cellules de la peau et la croissance tumorale

RSK2 as a key regulator in human skin cancer

Cho, Yong-Yeon ; Lee, Mee Hun ; Lee, Cheol-Jung ; Yao, Ke ; Lee, Hye Suk ; Bode, Ann M ; Dong, Zigang

Our previous report demonstrated that RSK2 plays an important role in cell proliferation and transformation induced by tumor promoters such as epidermal growth factor (EGF) mediated through the N-terminal kinase domain of RSK2 in JB6 Cl41 mouse skin epidermal cells in vitro. However, no direct evidence has been reported regarding the relationship of RSK2 activity and human skin cancer. To elucidate the relationship of RSK2 activity and human skin cancer, we examined the effect of knocking down [...]

Menée sur 165 patients atteints d'un adénocarcinome du poumon, cette étude met en évidence le rôle joué par la surexpression du gène ATAD2 dans la prolifération cellulaire incontrôlée, notamment chez les fumeurs

A comparative and integrative approach identifies ATPase family, AAA domain containing 2 as a likely driver of cell proliferation in lung adenocarcinoma

Fouret, Robert ; Laffaire, Julien ; Hofman, Paul ; Beau-Faller, Michèle ; Mazières, Julien ; Validire, Pierre ; Girard, Philippe ; Camilleri-Broet, Sophie ; Vaylet, Fabien ; Leroy-Ladurie, Francois ; Soria, Jean-Charles ; Fouret, Pierre

Purpose: To identify genetic changes that could drive cancer pathogenesis in never and ever smokers with lung adenocarcinoma. Experimental Design: We analyzed the copy-number and gene expression profiles of lung adenocarcinomas in 165 patients and related the alterations to smoking status. Having found differences in the tumor profiles, we integrated copy-number and gene expression data from 80 paired samples. Results: Amplifications at 8q24.12 overlapping MYC and ATAD2 were more frequent in [...]

Menée in vitro et sur des échantillons tumoraux prélevés sur des patients atteints de divers types de cancer, cette étude met en évidence des mécanismes par lesquels FAM83B joue un rôle d'oncogène

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

Cipriano, Rocky ; Graham, James ; Miskimen, Kristy L. S. ; Bryson, Benjamin L. ; Bruntz, Ronald C. ; Scott, Sarah A. ; Brown, H. Alex ; Stark, George R. ; Jackson, Mark W.

Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using validation-based insertional mutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), based on its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells (HMECs). We found that FAM83B coprecipitated with a downstream effector of [...]

Menée in vitro, cette étude identifie des micro-ARNs impliqués dans la régulation des cellules souches de cancer du sein

An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state

Polytarchou, Christos ; Iliopoulos, Dimitrios ; Struhl, Kevin

Cancer stem-like cells (CSCs) are a highly tumorigenic cell type present as a minority population in developmentally diverse tumors and cell lines. Using a genetic screen in an inducible model of CSC formation in a breast cell line, we identify microRNAs (miRNAs) that inhibit CSC growth and are down-regulated in CSCs. Aside from the previously identified miR-200 family, these include the miR-15/16 (miR-16, miR-15b) and miR-103/107 (miR-103, miR-107) families as well as miR-145, miR-335, and [...]

Menée in vitro, cette étude met en évidence le rôle joué par la protéine STMN1 dans le processus métastatique

Inhibition of Stathmin1 Accelerates the Metastatic Process

Williams, Karin ; Ghosh, Ritwik ; Vummidi Giridhar, Premkumar ; Gu, Guangyu ; Case, Thomas ; Belcher, Scott M ; Kasper, Susan

The oncoprotein Stathmin 1 (STMN1) is upregulated in most, if not all, cancers of epithelial cell origin; therefore STMN1 is considered a target for cancer therapy. However its role during metastasis has not been investigated. Here we report for the first time that STMN1 strongly inhibits metastatic behavior in both normal epithelial and cancerous epithelial cells. Initially, loss-of-STMN1 compromises cell-cell adhesion. This is followed by epithelial-to-mesenchymal-like transition (EMT), [...]

Menée sur 254 échantillons tumoraux prélevés sur des patientes atteintes d'un carcinome canalaire invasif du sein et à l'aide de xénogreffes, cette étude suggère que la surexpression de la protéine MRE11, impliquée dans des mécanismes de réparation de l'ADN, est associée à l'agressivité des tumeurs

Role of MRE11 in Cell Proliferation, Tumor Invasion, and DNA Repair in Breast Cancer

Yuan, Shyng-Shiou F. ; Hou, Ming-Feng ; Hsieh, Ya-Ching ; Huang, Chien-Yiu ; Lee, Yi-Chen ; Chen, Yun-Ju ; Lo, Steven

Background Previous studies have shown that altered forms of MRE11, a protein known to play a vital role in DNA double-strand break repair, DNA replication, and telomere maintenance are associated with cancer outcomes. We investigated the role of MRE11 in breast cancer in both clinical and in vitro settings.Methods We examined MRE11 expression in tumor tissues from invasive ductal carcinoma breast cancer patients (n = 254) by immunohistochemistry, and associations with clinicopathological [...]