A Feber

The multi-omic landscape of transcription factor inactivation in cancer

BackgroundHypermethylation of transcription factor promoters bivalently marked in stem cells is a cancer hallmark. However, the biological significance of this observation for carcinogenesis is unclear given that most of these transcription factors are not expressed in any given normal tissue.MethodsWe analysed the dynamics of gene expression between human embryonic stem cells, fetal and adult normal tissue, as well as six different matching cancer types. In addition, we performed an integrative multi-omic analysis of matched DNA methylation, copy number, mutational and transcriptomic data for these six cancer types.ResultsWe here demonstrate that bivalently and PRC2 marked transcription factors highly expressed in a normal tissue are more likely to be silenced in the corresponding tumour type compared with non-housekeeping genes that are also highly expressed in the same normal tissue. Integrative multi-omic analysis of matched DNA methylation, copy number, mutational and transcriptomic data for six different matching cancer types reveals that in-cis promoter hypermethylation, and not in-cis genomic loss or genetic mutation, emerges as the predominant mechanism associated with silencing of these transcription factors in cancer. However, we also observe that some silenced bivalently/PRC2 marked transcription factors are more prone to copy number loss than promoter hypermethylation, pointing towards distinct, mutually exclusive inactivation patterns.ConclusionsThese data provide statistical evidence that inactivation of cell fate-specifying transcription factors in cancer is an important step in carcinogenesis and that it occurs predominantly through a mechanism associated with promoter hypermethylation.

CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma

Other than an association with HPV infection, little is known about the genetic alterations determining the development of penile cancer. Although penile cancer is rare in the developed world, it presents a significant burden in developing countries. Here, we report the findings of whole-exome sequencing (WES) to determine the somatic mutational landscape of penile cancer. WES was performed on penile cancer and matched germline DNA from 27 patients undergoing surgical resection. Targeted resequencing of candidate genes was performed in an independent 70 patient cohort. Mutation data were also integrated with DNA methylation and copy-number information from the same patients. We identified an HPV-associated APOBEC mutation signature and an NpCpG signature in HPV-negative disease. We also identified recurrent mutations in the novel penile cancer tumor suppressor genes CSN1(GPS1) and FAT1 Expression of CSN1 mutants in cells resulted in colocalization with AGO2 in cytoplasmic P-bodies, ultimately leading to the loss of miRNA-mediated gene silencing, which may contribute to disease etiology. Our findings represent the first comprehensive analysis of somatic alterations in penile cancer, highlighting the complex landscape of alterations in this malignancy. Cancer Res; 76(16); 4720-7. ©2016 AACR.

A novel cell-type deconvolution algorithm reveals substantial contamination by immune cells in saliva, buccal and cervix

AIMnAn outstanding challenge in epigenome studies is the estimation of cell-type proportions in complex epithelial tissues.nnnMATERIALS & METHODSnHere, we construct and validate a DNA methylation reference and algorithm for complex tissues that contain epithelial, immune and nonimmune stromal cells.nnnRESULTSnUsing this reference, we show that easily accessible tissues such as saliva, buccal and cervix exhibit substantial variation in immune cell (IC)xa0contamination. We further validate our reference in the context of oral cancer, where it correctly predicts an increased IC infiltration in cancer but suppressed in patients with highest smoking exposure. Finally, our method can improve the specificity of differentially methylated CpG calls in epithelial cancer.nnnCONCLUSIONnThe degree and variation of IC contamination in complex epithelial tissues is substantial. We provide a valuable resource and tool for assessing the epithelial purity and IC contamination of samples and for identifying differential methylation in such complex tissues.

51 Epigenetic alterations associated with neo-adjuvant chemotherapy resistance in bladder cancer

INTRODUCTION & OBJECTIVES: Neoadjuvant cisplatin based chemotherapy is recommended for patients with muscle invasive bladder cancer. Cisplatin based regimes have similar efficacy with complete response in 30% a survival advantage if 16% (HR, 0.84;CI 0.72 to 0.99). The ability to identify a biomarker which is able to predict response to treatment would increase pathological complete response rates and spare nonresponders adverse events of chemotherapy. DNA hypermethylation has been implicated in chemotherapy resistance in cancers. We hypothesised that DNA methylation may not only represent the mechanisms for the acquisition of resistance, but may also be a potential biomarker to predict response to platinum based chemotherapy in bladder cancer.