Genome-wide identification of key modulators of gene-gene interaction networks in breast cancer
Journal
BMC Genomics
Pages
e1602783
Date Issued
2017
Author(s)
Abstract
Background: With the advances in high-throughput gene profiling technologies, a large volume of gene interaction maps has been constructed. A higher-level layer of gene-gene interaction, namely modulate gene interaction, is composed of gene pairs of which interaction strengths are modulated by (i.e., dependent on) the expression level of a key modulator gene. Systematic investigations into the modulation by estrogen receptor (ER), the best-known modulator gene, have revealed the functional and prognostic significance in breast cancer. However, a genome-wide identification of key modulator genes that may further unveil the landscape of modulated gene interaction is still lacking. Results: We proposed a systematic workflow to screen for key modulators based on genome-wide gene expression profiles. We designed four modularity parameters to measure the ability of a putative modulator to perturb gene interaction networks. Applying the method to a dataset of 286 breast tumors, we comprehensively characterized the modularity parameters and identified a total of 973 key modulator genes. The modularity of these modulators was verified in three independent breast cancer datasets. ESR1, the encoding gene of ER, appeared in the list, and abundant novel modulators were illuminated. For instance, a prognostic predictor of breast cancer, SFRP1, was found the second modulator. Functional annotation analysis of the 973 modulators revealed involvements in ER-related cellular processes as well as immune- and tumor-associated functions. Conclusions: Here we present, as far as we know, the first comprehensive analysis of key modulator genes on a genome-wide scale. The validity of filtering parameters as well as the conservativity of modulators among cohorts were corroborated. Our data bring new insights into the modulated layer of gene-gene interaction and provide candidates for further biological investigations. ? 2017 The Author(s).
Subjects
Breast cancer; Gene interaction networks; Genome-wide analysis; Modulated gene interactions; Modulator genes
SDGs
Other Subjects
estrogen receptor; monocarboxylate transporter 1; protein kinase Lyn; secreted frizzled related protein 1; Article; ATP5G2 gene; breast cancer; cancer prognosis; CRYAB gene; CYFIP2 gene; disease association; ESR1 gene; FAIM3 gene; GABRP gene; gene; gene expression; gene identification; gene interaction; gene regulatory network; genetic code; genome-wide association study; GPM6B gene; human; IFRD1 gene; ITM2A gene; KANK1 gene; LY75 gene; POLD4 gene; PPP1CB gene; predictor variable; SERPINB5 gene; SFRP1 gene; SLC16A1 gene; SYNM gene; TMEM158 gene; UBE2E3 gene; breast tumor; gene expression profiling; gene regulatory network; genetics; genomics; Breast Neoplasms; Gene Expression Profiling; Gene Regulatory Networks; Genomics; Humans
Type
journal article