Aging-associated alterations in gene regulatory networks associate with risk, prognosis and response to therapy in lung adenocarcinoma.

Abstract

Aging is the primary risk factor for many cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival, we built individual-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for non-cancerous lung samples from GTEx project and LUAD samples from TCGA. In healthy lung, pathways involved in cell proliferation and immune response were increasingly targeted with age; these aging-associated alterations were accelerated by smoking and resembled oncogenic shifts observed in LUAD. Aging-associated genes showed greater aging-biased targeting patterns in individuals with LUAD compared to healthier counterparts, a pattern suggestive of age acceleration. Using drug repurposing tool CLUEreg, we found small molecule drugs that may potentially alter the accelerating aging profiles we found. We defined a network-informed aging signature that was associated with survival in LUAD.