The ability of an organ's stem cells to generate new tissue over time — the cells' generative capacity — determines how prone that organ is to cancer. Scientists have debated the relative importance of factors that contribute to an organ's cancer risk, including 'intrinsic' factors such as the number of stem-cell divisions and 'extrinsic' factors that cause tissue and DNA damage. To compare these factors, Richard Gilbertson at the CRUK Cambridge Institute, UK, Arzu Onar-Thomas at St Jude Children's Research Hospital in Memphis, Tennessee, and their colleagues studied stem cells called Prom1+ cells with varying levels of generative capacity in different organs in mice of various ages. The authors introduced key cancer-causing mutations into the cells, then looked for tumour growth in the organs. The team found that cancer risk correlated closely with the generative capacity of the Prom1+ cells. In liver tissue, cancer mutations alone did not cause cancer — tissue injury significantly increased cancer susceptibility. The authors propose that several factors contribute to a 'perfect storm' of tumour growth: mutated stem cells and extrinsic factors that trigger cell proliferation.
Chabbert C.D.,Genome Biology Unit |
Chabbert C.D.,CRUK Cambridge Institute |
Steinmetz L.M.,Genome Biology Unit |
Steinmetz L.M.,Stanford University |
Klaus B.,Genome Biology Unit
PeerJ | Year: 2016
The genome-wide study of epigenetic states requires the integrative analysis of histone modification ChIP-seq data. Here, we introduce an easy-to-use analytic framework to compare profiles of enrichment in histone modifications around classes of genomic elements, e.g. transcription start sites (TSS). Our framework is available via the user-friendly R/Bioconductor package DChIPRep. DChIPRep uses biological replicate information as well as chromatin Input data to allow for a rigorous assessment of differential enrichment. DChIPRep is available for download through the Bioconductor project at http://bioconductor.org/packages/DChIPRep. © 2016 Chabbert et al.
Severson T.M.,Netherlands Cancer Institute |
Peeters J.,Agendia Inc. |
Majewski I.,Netherlands Cancer Institute |
Majewski I.,Walter and Eliza Hall Institute of Medical Research |
And 17 more authors.
Molecular Oncology | Year: 2015
Triple negative (TN) breast cancers make up some 15% of all breast cancers. Approximately 10-15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required for homologous recombination-mediated DNA repair and deficiency results in genomic instability. BRCA1-mutated tumors have a specific pattern of genomic copy number aberrations that can be used to classify tumors as BRCA1-like or non- BRCA1-like. BRCA1 mutation, promoter methylation, BRCA1-like status and genome-wide expression data was determined for 112 TN breast cancer samples with long-term follow-up. Mutation status for 21 known DNA repair genes and PIK3CA was assessed. Gene expression and mutation frequency in BRCA1-like and non- BRCA1-like tumors were compared. Multivariate survival analysis was performed using the Cox proportional hazards model. BRCA1 germline mutation was identified in 10% of patients and 15% of tumors were BRCA1 promoter methylated. Fifty-five percent of tumors classified as BRCA1-like. The functions of genes significantly up-regulated in BRCA1-like tumors included cell cycle and DNA recombination and repair. TP53 was found to be frequently mutated in BRCA1-like (P < 0.05), while PIK3CA was frequently mutated in non- BRCA1-like tumors (P < 0.05). A significant association with worse prognosis was evident for patients with BRCA1-like tumors (adjusted HR = 3.32, 95% CI = 1.30-8.48, P = 0.01). TN tumors can be further divided into two major subgroups, BRCA1-like and non-BRCA1-like with different mutation and expression patterns and prognoses. Based on these molecular patterns, subgroups may be more sensitive to specific targeted agents such as PI3K or PARP inhibitors. © 2015 The Authors.
Pertega-Gomes N.,CRUK Cambridge Institute |
Vizcaino J.R.,Centro Hospitalar do Porto |
Felisbino S.,Sao Paulo State University |
Warren A.Y.,University of Cambridge |
And 10 more authors.
Oncotarget | Year: 2015
Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.