Lessons from the Cancer Genome
ABSTRACT Systematic studies of the cancer genome have exploded in recent years. These studies have revealed scores of new cancer genes, including many in processes not previously known to be causal targets in cancer. The genes affect cell signaling, chromatin, and epigenomic regulation; RNA splicing; protein homeostasis; metabolism; and lineage maturation. Still, cancer genomics is in its infancy. Much work remains to complete the mutational catalog in primary tumors and across the natural history of cancer, to connect recurrent genomic alterations to altered pathways and acquired cellular vulnerabilities, and to use this information to guide the development and application of therapies.
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ABSTRACT: Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma and of the potential role of DNA methylation markers as prognostic biomarkers. The analysis of tumor tissue from 304 patients with hepatocellular carcinoma treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array, which covers 96% of known CpG islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate and miRNA Chip 2.0. Random Survival Forest enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient's survival both in the training set (221 patients; 47% hepatitis C-related hepatocellular carcinoma) and validation sets (n=83; 47% alcohol-related hepatocellular carcinoma). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known de-regulated by aberrant methylation in hepatocellular carcinoma (e.g. RASSF1, IGF2, APC) and other solid tumors (e.g. NOTCH3), and describe potential candidate epidrivers (e.g. SEPT9, EFNB2). Conclusions: A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with hepatocellular carcinoma. Patients with this methylation profile harbor mRNA-based signatures indicating tumors with progenitor cell features. This article is protected by copyright. All rights reserved.Hepatology 02/2015; 61(6). DOI:10.1002/hep.27732 · 11.19 Impact Factor
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ABSTRACT: In 2003, Human Mutation published its first special issue on TP53 (Soussi, 2003; http://onlinelibrary.wiley.com/doi/10.1002/humu.v21:3/issuetoc). That issue included the most exhaustive series of reviews devoted to the analysis of TP53 mutations in various types of cancer ever published. Furthermore, thanks to the expertise of the various authors, the quality of the data makes those reviews still highly accurate and up to date.Human Mutation 06/2014; 35(6). DOI:10.1002/humu.22562 · 5.05 Impact Factor
Article: TP53: an oncogene in disguise[Show abstract] [Hide abstract]
ABSTRACT: The standard classification used to define the various cancer genes confines tumor protein p53 (TP53) to the role of a tumor suppressor gene. However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins. This statement is based on multiple arguments including the mutation signature of the TP53 gene in human cancer, the various gains-of-function (GOFs) of the different p53 mutants and the heterogeneous phenotypes developed by knock-in mouse strains modeling several human TP53 mutations. In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated. Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors. The use of Muller's classical definition of mutations based on quantitative and qualitative consequences on the protein product, such as 'amorph', 'hypomorph', 'hypermorph' 'neomorph' or 'antimorph', allows a more meaningful assessment of the consequences of cancer gene modifications, their potential clinical significance, and clearly demonstrates that the TP53 gene is an atypical cancer gene.Cell Death and Differentiation advance online publication, 29 May 2015; doi:10.1038/cdd.2015.53.Cell death and differentiation 05/2015; DOI:10.1038/cdd.2015.53 · 8.39 Impact Factor