Subtype-specific transcriptional regulators in breast tumors subjected to genetic and epigenetic alterations.

Qian Zhu,Olga G Troyanskaya,Vessela N Kristensen,Xavier Tekpli,Russell Schwartz

doi:10.1093/bioinformatics/btz709

Abstract

MotivationBreast cancer consists of multiple distinct tumor subtypes, and results from epigenetic and genetic aberrations that give rise to distinct transcriptional profiles. Despite previous efforts to understand transcriptional deregulation through transcription factor networks, the transcriptional mechanisms leading to subtypes of the disease remain poorly understood.ResultsWe used a sophisticated computational search of thousands of expression datasets to define extended signatures of distinct breast cancer subtypes. Using ENCODE ChIP-seq data of surrogate cell lines and motif analysis we observed that these subtypes are determined by a distinct repertoire of lineage-specific transcription factors. Furthermore, specific pattern and abundance of copy number and DNA methylation changes at these TFs and targets, compared to other genes and to normal cells were observed. Overall, distinct transcriptional profiles are linked to genetic and epigenetic alterations at lineage-specific transcriptional regulators in breast cancer subtypes.Availability and implementationThe analysis code and data are deposited at https://bitbucket.org/qzhu/breast.cancer.tf/.Supplementary information Supplementary data are available at Bioinformatics online.

Highlights

Tumorigenesis in breast cancer is thought to be the result of a combination of somatic genetic events including copy number alterations (CNA), point mutations and epigenetic alterations such as DNA methylation (DNAme)
ChIP-seq measures experimental binding while motif, coexpression evidence are designed to expand the scope of inferable transcription factor (TF) from ENCODE by a search of additional motifs that may be overrepresented in the regulatory regions of extended subtype-specific gene signatures (ESG) (Section 2)
The unbiased search of ChIP-seq experiments, where the sum of binding intensities at the regulatory regions of the subtype-specific ESGs were significantly higher than binding at random genes, identified the three well-known luminal A-associated TFs: Esr1, Gata3 and Foxa1 (Fig. 1)

Summary

Introduction

Tumorigenesis in breast cancer is thought to be the result of a combination of somatic genetic events including copy number alterations (CNA), point mutations and epigenetic alterations such as DNA methylation (DNAme). Aberrations in breast cancer are manifested in a subtype-specific manner, and distinct biological processes are uniquely perturbed in these subtypes (Curtis et al, 2012; NikZainal et al, 2012). Because of the distinct expression profiles, it is thought that the development of cancer involves the combinatorial effects of transcription factors expressed in a coordinated manner. Together they evolve downstream of germ-line and somatic genetic events and subtype-specific regulators can further give rise to the subtype-specific co-expression of downstream target genes

Methods

Results

Conclusion