DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events.

While large-scale studies applying various statistical approaches have identified hundreds of mutated driver genes across various cancer types, the contribution of epigenetic changes to cancer remains more enigmatic. This is partly due to the fact that certain regions of the cancer genome, due to their genomic and epigenomic properties, are more prone to dysregulated DNA methylation than others. Thus, it has been difficult to distinguish which promoter methylation changes are really driving carcinogenesis from those that are mostly just a reflection of their genomic location. By developing a novel method that corrects for epigenetic covariates, we reveal a small, concise set of potential epigenetic driver events. Interestingly, those changes suggest different modes of epigenetic carcinogenesis: first, we observe recurrent inactivation of known cancer genes across tumour types suggesting a higher convergence on common tumour suppressor pathways than previously anticipated. Second, in prostate cancer, a cancer type with few recurrently mutated genes, we demonstrate how the epigenome primes tumours towards higher tolerance of other aberrations.

In Silico and In Vitro Analyses of LncRNAs as Potential Regulators in the Transition from the Epithelioid to Sarcomatoid Histotype of Malignant Pleural Mesothelioma (MPM).

Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. At present, treatment options are limited, with no second line chemotherapy for those who fail first line therapy. Extensive efforts are ongoing in a bid to characterise the underlying molecular mechanisms of mesothelioma. Recent research has determined that between 70⁻90% of our genome is transcribed. As only 2% of our genome is protein coding, the roles of the remaining proportion of non-coding RNA in biological processes has many applications, including roles in carcinogenesis and epithelial⁻mesenchymal transition (EMT), a process thought to play important roles in MPM pathogenesis. Non-coding RNAs can be separated loosely into two subtypes, short non-coding RNAs (<200 nucleotides) or long (>200 nucleotides). A significant body of evidence has emerged for the roles of short non-coding RNAs in MPM. Less is known about the roles of long non-coding RNAs (lncRNAs) in this disease setting. LncRNAs have been shown to play diverse roles in EMT, and it has been suggested that EMT may play a role in the aggressiveness of MPM histological subsets. In this report, using both in vitro analyses on mesothelioma patient material and in silico analyses of existing RNA datasets, we posit that various lncRNAs may play important roles in EMT within MPM, and we review the current literature regarding these lncRNAs with respect to both EMT and MPM.

Long Non-Coding RNAs: Key Regulators of Epithelial-Mesenchymal Transition, Tumour Drug Resistance and Cancer Stem Cells.

Epithelial mesenchymal transition (EMT), the adoption by epithelial cells of a mesenchymal-like phenotype, is a process co-opted by carcinoma cells in order to initiate invasion and metastasis. In addition, it is becoming clear that is instrumental to both the development of drug resistance by tumour cells and in the generation and maintenance of cancer stem cells. EMT is thus a pivotal process during tumour progression and poses a major barrier to the successful treatment of cancer. Non-coding RNAs (ncRNA) often utilize epigenetic programs to regulate both gene expression and chromatin structure. One type of ncRNA, called long non-coding RNAs (lncRNAs), has become increasingly recognized as being both highly dysregulated in cancer and to play a variety of different roles in tumourigenesis. Indeed, over the last few years, lncRNAs have rapidly emerged as key regulators of EMT in cancer. In this review, we discuss the lncRNAs that have been associated with the EMT process in cancer and the variety of molecular mechanisms and signalling pathways through which they regulate EMT, and finally discuss how these EMT-regulating lncRNAs impact on both anti-cancer drug resistance and the cancer stem cell phenotype.