Molecular Biology Networks and Key Gene Regulators for Inflammatory Biomarkers Shared by Breast Cancer Development: Multi-Omics Systems Analysis

Abstract

As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor provided comprehensive understanding of the underlying regulatory mechanisms. We adopted an integrative genomic network approach by incorporating our previous GWAS data for CRP and IL6 with multi-omics datasets, such as whole-blood expression quantitative loci, molecular biologic pathways, and gene regulatory networks to capture the full range of genetic functionalities associated with CRP/IL6 and tissue-specific key drivers (KDs) in gene subnetworks. We applied another systematic genomics approach for BC development to detect shared gene sets in enriched subnetworks across BC and CRP/IL6. We detected the topmost significant common pathways across CRP/IL6 (e.g., immune regulatory; chemokines and their receptors; interferon γ, JAK-STAT, and ERBB4 signaling), several of which overlapped with BC pathways. Further, in gene–gene interaction networks enriched by those topmost pathways, we identified KDs—both well-established (e.g., JAK1/2/3, STAT3) and novel (e.g., CXCR3, CD3D, CD3G, STAT6)—in a tissue-specific manner, for mechanisms shared in regulating CRP/IL6 and BC risk. Our study may provide robust, comprehensive insights into the mechanisms of CRP/IL6 regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for associated disorders, such as BC.

Combining TNFR2-Expressing Tregs and IL-6 as Superior Diagnostic Biomarkers for High-Grade Serous Ovarian Cancer Masses

“…The IL-6-and TNFR2-associated pathways are emerging as critical mediators of inflammation-associated cancers, including ovarian malignancy [30,64,70,71,[76][77][78][79][80]. In our study, we found a significant overlapping contribution of TNFR2-expressing Tregs and IL-6 in predicting ovarian malignancy.…”

Shared Genetic Regulatory Networks Contribute to Neuropathic and Inflammatory Pain: Multi-Omics Systems Analysis

“…We aggregated the modules for each pathway in NP and IP separately. We then merged the modules from NP and IP for an overlapping pathway where more than 15% of genes are overlapped in both NP and IP and created 47 functionally categorized supernets [ 33 ].…”