Gene regulatory network analysis identifies sex-linked differences in colon cancer drug metabolism processes

Significant sex differences are observed in colon cancer, and understanding these differences is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. We used both transcript-based and gene regulatory network methods to analyze RNA-Seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and found no significant sex differences except for sex-chromosome genes. We then inferred patient-specific gene regulatory networks, and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset that included 1,193 patients from five independent studies. While targeting of the drug metabolism pathway did not change the overall survival for males treated with adjuvant chemotherapy, females with greater targeting had an increase in 10-year overall survival probability, with 89% (95% CI: 78%-100%) survival compared to 61% (95% CI: 45%-82%) for women with lower targeting, respectively (p=0.034). Our network analysis uncovered patterns of transcriptional regulation that differentiate male and female colon cancer. Most importantly, targeting of the drug metabolism pathway was predictive of survival in women who received adjuvant chemotherapy. This network-based approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.