Menée sur des échantillons tumoraux prélevés sur 67 patients atteints d'un carcinome hépatocellulaire associé au virus de l'hépatite B ou au virus de l'hépatite C, cette étude italienne analyse la fréquence des mutations des gènes TP53, CTNNB1 et PIK3CA

Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections

Tornesello, Maria Lina ; Buonaguro, Luigi ; Tatangelo, Fabiana ; Botti, Gerardo ; Izzo, Francesco ; Buonaguro, Franco M.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Hepatocarcinogenesis is a multistep process mainly associated with persistent infection with hepatitis B (HBV) or C (HCV) viruses and always involving the accumulation of genetic alterations over decades of chronic liver disease. Mutations in TP53 and CTNNB1 genes are considered the cancer drivers for HCC development with variable frequencies depending on the etiology. Here we present a comprehensive review [...]

Menée sur des échantillons hépatiques prélevés sur 401 patients (305 carcinomes, 60 adénomes typiques, 16 adénomes avec signes de transformation maligne, 20 nodules prénéoplasiques cirrhotiques), cette étude française identifie de fréquentes mutations du promoteur du gène TERT dans les lésions prénéoplasiques de foies cirrhotiques et dans les carcinomes hépatocellulaires

High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions

Nault, Jean Charles ; Mallet, Maxime ; Pilati, Camilla ; Calderaro, Julien ; Bioulac-Sage, Paulette ; Laurent, Christophe ; Laurent, Alexis ; Cherqui, Daniel ; Balabaud, Charles ; Rossi, Jessica Zucman

Somatic mutations activating telomerase reverse-trancriptase promoter were recently identified in several tumour types. Here we identify frequent similar mutations in human hepatocellular carcinomas (59%), cirrhotic preneoplastic macronodules (25%) and hepatocellular adenomas with malignant transformation in hepatocellular carcinomas (44%). In hepatocellular tumours, telomerase reverse-transcripase- and CTNNB1-activating mutations are significantly associated. Moreover, preliminary data suggest [...]

Menée sur des échantillons tumoraux prélevés sur des patients atteints de cancer (système nerveux central, vessie, thyroïde, mélanome), cette étude met en évidence de fréquentes mutations du promoteur du gène TERT, ce qui induit une surexpression de la télomérase

Frequency of TERT promoter mutations in human cancers

Vinagre, João ; Almeida, Ana ; Pópulo, Helena ; Batista, Rui ; Lyra, Joana ; Pinto, Vasco ; Coelho, Ricardo ; Celestino, Ricardo ; Prazeres, Hugo ; Lima, Luis ; Melo, Miguel ; Rocha, Adriana Gaspar da ; Preto, Ana ; Castro, Patrícia ; Castro, Ligia ; Pardal, Fernando ; Lopes, José Manuel ; Santos, Lúcio Lara ; Reis, Rui Manuel ; Cameselle-Teijeiro, José ; Sobrinho-Simões, Manuel ; Lima, Jorge ; Máximo, Valdemar ; Soares, Paula

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA [...]

A partir d'échantillons prélevés sur des patients pédiatriques atteints d'une leucémie lymphoblastique aiguë pro-B présentant une fusion des gènes MLL-AF4, cette étude de séquençage du génome entier montre que la maladie est associée à un très petit nombre de mutations somatiques

The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia

Dobbins, Sara E. ; Sherborne, Amy L. ; Ma, Yussanne P. ; Bardini, Michela ; Biondi, Andrea ; Cazzaniga, Giovanni ; Lloyd, Amy ; Chubb, Daniel ; Greaves, Mel F. ; Houlston, Richard S.

Over 90% of infants (<1-year-old) diagnosed with leukemia have pro-B acute lymphoblastic leukemia (ALL) containing the MLL-AF4 fusion. When compared with other forms of paediatric ALL affecting later B-cell differentiation, MLL-AF4 pro-B is associated with a dismal prognosis with a typical 5-year disease-free survival of <20%. MLL-AF4 may be sufficient on its own for leukemogenesis or the gene-fusion product may alternatively predispose transformed cells to global genetic instability, enhancing [...]

Menée initialement sur 29 échantillons tumoraux prélevés sur des patients atteints de mélanome, puis sur 285 échantillons complémentaires, cette étude identifie une fréquente mutation somatique synonyme (affectant un exon sans modifier la séquence de la protéine) du gène BCL2L12 et met notamment en évidence une inhibition plus efficace de l'apoptose par la protéine issue du gène muté

Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma

Gartner, Jared J. ; Parker, Stephen C. J. ; Prickett, Todd D. ; Dutton-Regester, Ken ; Stitzel, Michael L. ; Lin, Jimmy C. ; Davis, Sean ; Simhadri, Vijaya L. ; Jha, Sujata ; Katagiri, Nobuko ; Gotea, Valer ; Teer, Jamie K. ; Wei, Xiaomu ; Morken, Mario A. ; Bhanot, Umesh K. ; NISC Comparative Sequencing Program ; Chen, Guo ; Elnitski, Laura L. ; Davies, Michael A. ; Gershenwald, Jeffrey E. ; Carter, Hannah ; Karchin, Rachel ; Robinson, William ; Robinson, Steven ; Rosenberg, Steven A. ; Collins, Francis S. ; Parmigiani, Giovanni ; Komar, Anton A. ; Kimchi-Sarfaty, Chava ; Hayward, Nicholas K. ; Margulies, Elliott H. ; Samuels, Yardena

Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683–691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This [...]

Menée sur 97 échantillons tumoraux prélevés sur des patients atteints d'un cancer de la vessie de haut grade, cette étude analyse la prévalence des anomalies génomiques susceptibles de prédire la réponse à une thérapie ciblée

Prevalence and Co-Occurrence of Actionable Genomic Alterations in High-Grade Bladder Cancer

Iyer, Gopa ; Al-Ahmadie, Hikmat ; Schultz, Nikolaus ; Hanrahan, Aphrothiti J. ; Ostrovnaya, Irina ; Balar, Arjun V. ; Kim, Philip H. ; Lin, Oscar ; Weinhold, Nils ; Sander, Chris ; Zabor, Emily C. ; Janakiraman, Manickam ; Garcia-Grossman, Ilana R. ; Heguy, Adriana ; Viale, Agnes ; Bochner, Bernard H. ; Reuter, Victor E. ; Bajorin, Dean F. ; Milowsky, Matthew I. ; Taylor, Barry S. ; Solit, David B.

Purpose We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery. Patients and Methods An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the [...]

Menée sur des lignées cellulaires de divers types de cancer, cette étude suggère que le gène CMTM7, localisé sur une région chromosomique fréquemment délétée (3p12-22), est un suppresseur de tumeurs

A novel 3p22.3 gene CMTM7 represses oncogenic EGFR signaling and inhibits cancer cell growth

Li, H. ; Li, J. ; Su, Y. ; Fan, Y. ; Guo, X. ; Li, L. ; Su, X. ; Rong, R. ; Ying, J. ; Mo, X. ; Liu, K. ; Zhang, Z. ; Yang, F. ; Jiang, G. ; Wang, J. ; Zhang, Y. ; Ma, D. ; Tao, Q. ; Han, W.

Deletion of 3p12-22 is frequent in multiple cancer types, indicating the presence of critical tumor-suppressor genes (TSGs) at this region. We studied a novel candidate TSG, CMTM7, located at the 3p22.3 CMTM-gene cluster, for its tumor-suppressive functions and related mechanisms. The three CMTM genes, CMTM6, 7 and 8, are broadly expressed in human normal adult tissues and normal epithelial cell lines. Only CMTM7 is frequently silenced or downregulated in esophageal and nasopharyngeal cell [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en régulant la réponse des cellules épithéliales de la prostate à un dégât de l'ADN, le gène NKX3.1 joue un rôle de suppresseur de tumeurs

Functional Activation of ATM by the Prostate Cancer Suppressor NKX3.1

Bowen, Cai ; Ju, Jeong-Ho ; Lee, Ji-Hoon ; Paull, Tanya T ; Gelmann, Edward P

The prostate tumor suppressor NKX3.1 augments response to DNA damage and enhances survival after DNA damage. Within minutes of DNA damage, NKX3.1 undergoes phosphorylation at tyrosine 222, which is required for a functional interaction with ataxia telangiectasia mutated (ATM) kinase. NKX3.1 binds to the N-terminal region of ATM, accelerates ATM activation, and hastens the formation of ³histone2AX. NKX3.1 enhances DNA-dependent ATM kinase activation by both the MRN complex and H2O2 in a [...]

Menée in vitro et in vivo, cette étude met en évidence un processus de nature inflammatoire qui, en fonction de l'activité de p53, est susceptible de réprimer ou de favoriser la tumorigenèse

A Senescence-Inflammatory Switch from Cancer-Inhibitory to Cancer-Promoting Mechanism

Pribluda, Ariel ; Elyada, Ela ; Wiener, Zoltan ; Hamza, Haya ; Goldstein, Robert E ; Biton, Moshe ; Burstain, Ido ; Morgenstern, Yael ; Brachya, Guy ; Billauer, Hana ; Biton, Sharon ; Snir-Alkalay, Irit ; Vucic, Domagoj ; Schlereth, Katharina ; Mernberger, Marco ; Stiewe, Thorsten ; Oren, Moshe ; Alitalo, Kari ; Pikarsky, Eli ; Ben-Neriah, Yinon

Senescence, perceived as a cancer barrier, is paradoxically associated with inflammation, which promotes tumorigenesis. Here, we characterize a distinct low-grade inflammatory process in stressed epithelium that is related to para-inflammation; this process either represses or promotes tumorigenesis, depending on p53 activity. Csnk1a1 (CKI±) downregulation induces a senescence-associated inflammatory response (SIR) with growth arrest in colorectal tumors, which loses its growth control capacity [...]

Menée sur des lignées cellulaires de sarcome, cette étude met en évidence des mécanismes par lesquels le micro-ARN 129 favorise l'expression du gène suppresseur de tumeurs A20

miR-29 Acts as a Decoy in Sarcomas to Protect the Tumor Suppressor A20 mRNA from Degradation by HuR

Yaseen Balkhi, Mumtaz ; Iwenofu, O. Hans ; Bakkar, Nadine ; Ladner, Katherine J. ; Chandler, Dawn S. ; Houghton, Peter J. ; London, Cheryl A. ; Kraybill, William ; Perrotti, Danilo ; Croce, Carlo M. ; Keller, Charles ; Guttridge, Denis C.

In sarcoma, the activity of NF-{kappa}B (nuclear factor {kappa}B) reduces the abundance of the microRNA (miRNA) miR-29. The tumor suppressor A20 [also known as TNFAIP3 (tumor necrosis factor–

Cet article passe en revue les travaux récents sur le rôle de la signalisation PI3K dans les mécanismes d'interaction entre des cellules tumorales et leur micro-environnement

PI3K in cancer-stroma interactions: bad in seed and ugly in soil

Hirsch, E. ; Ciraolo, E. ; Franco, I. ; Ghigo, A. ; Martini, M.

Over the past decade the phosphoinositide-3 kinase (PI3K) signaling pathway emerged as an important player for tumor initiation and growth and, currently, PI3K inhibition constitutes a promising therapeutic approach for solid and hematological tumors. Beside its role in tumor cell evolution, PI3K signaling also provides integral functions for noncancerous cells that reside in healthy tissues surrounding the tumor, also referred as tumor microenvironment (TME). This review will address how PI3K [...]

Menée à l'aide de modèles murins et sur des échantillons de moelle osseuse prélevés sur 16 patients atteints d'une leucémie myéloïde aiguë, cette étude montre que la maladie n'est pas associée à une déplétion de cellules souches hématopoïétiques mais à l'inhibition de leur différenciation

Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation

Miraki-Moud, Farideh ; Anjos-Afonso, Fernando ; Hodby, Katharine A. ; Griessinger, Emmanuel ; Rosignoli, Guglielmo ; Lillington, Debra ; Jia, Li ; Davies, Jeff K. ; Cavenagh, Jamie ; Smith, Matthew ; Oakervee, Heather ; Agrawal, Samir ; Gribben, John G. ; Bonnet, Dominique ; Taussig, David C.

Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding. The mechanism by which AML mediates this complication is unknown but one widely accepted explanation is that AML depletes the BM of hematopoietic stem cells (HSCs) through displacement. We sought to investigate how AML affects hematopoiesis by quantifying residual normal hematopoietic subpopulations in the BM of immunodeficient mice transplanted with human [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la kinase SPHK1 dans l'interaction entre les cellules de mélanome et leur micro-environnement

Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells

Albinet, V. ; Bats, M. L. ; Huwiler, A. ; Rochaix, P. ; Chevreau, C. ; Segui, B. ; Levade, T. ; Andrieu-Abadie, N.

Despite progress in the understanding of the biology and genetics of melanoma, no effective treatment against this cancer is available. The adjacent microenvironment has an important role in melanoma progression. Defining the molecular signals that control the bidirectional dialog between malignant cells and the surrounding stroma is crucial for efficient targeted therapy. Our study aimed at defining the role of sphingosine-1-phosphate (S1P) in melanoma–stroma interactions. Transcriptomic [...]