The validation dataset contained five independent studies: GSE14333, GSE17538, GSE33113, GSE37892, and GSE39582. We searched the Gene Expression Omnibus (GEO) repository for colon cancer studies that included patient survival data and were obtained from the same microarray platform (Affymetrix Human Genome U133 Plus 2.0 Array). Pharmacokinetics also vary between the sexes females experience greater toxicity from certain chemotherapies, including 5-FU, consistent with the lower 5-FU clearance observed in females ( 8, 9). Furthermore, females have a higher survival benefit from 5-fluorouracil (5-FU)–based adjuvant chemotherapy as compared with males ( 7). In colon cancer, females not only have reduced risk relative to males, but also have a better prognosis ( 4–6). Even though the higher risk in males might be attributed partially to occupational exposures and/or behavioral factors, such as diet, smoking, and alcohol consumption, after adjusting for these risk factors males still have a higher cancer risk, although residual confounding cannot be excluded ( 1–3). For many cancer types, such as colon, skin, head and neck, esophagus, lung, and liver, males have a higher risk and higher mortality rates than females ( 1). Significant differences between the sexes are observed during the development and progression of diseases, influencing disease incidence and survival. This approach can be used to understand how sex influences progression and response to therapies in other cancers. Significance: A network-based approach reveals that sex-specific patterns of gene targeting by transcriptional regulators are associated with survival outcome in colon cancer. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases. Our network analysis uncovers patterns of transcriptional regulation that differentiate male and female colon cancer and identifies differences in regulatory processes involving the drug metabolism pathway associated with survival in women who receive adjuvant chemotherapy. While targeting, the drug metabolism pathway did not change overall survival for males treated with adjuvant chemotherapy, females with greater targeting showed an increase in 10-year overall survival probability, 89% survival compared with 61% (95% CI, 45–82) for women with lower targeting, respectively ( P = 0.034). This finding was validated in a dataset of 1,193 patients from five independent studies. 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. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. In this study, we use both transcript-based and gene regulatory network methods to analyze RNA-seq data from The Cancer Genome Atlas for 445 patients with colon cancer. However, the molecular features that drive these sex differences are poorly understood. Males have a higher risk of developing colon cancer and a lower survival rate than women. Understanding sex differences in colon cancer is essential to advance disease prevention, diagnosis, and treatment.
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