Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism.
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Abstract | Understanding sex differences in colon cancer 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. 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. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. 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 of 1,193 patients from five independent studies. 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% [95% confidence interval (CI), 78-100] survival compared with 61% (95% CI, 45-82) for women with lower targeting, respectively ( = 0.034). 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. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases. 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 understand how sex influences progression and response to therapies in other cancers. . |
Year of Publication | 2018
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Journal | Cancer Res
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Volume | 78
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Issue | 19
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Pages | 5538-5547
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Date Published | 2018 10 01
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ISSN | 1538-7445
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DOI | 10.1158/0008-5472.CAN-18-0454
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PubMed ID | 30275053
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PubMed Central ID | PMC6169995
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Grant list | R35 CA197735 / CA / NCI NIH HHS / United States
R35 CA197449 / CA / NCI NIH HHS / United States
K25 HL133599 / HL / NHLBI NIH HHS / United States
R01 CA205406 / CA / NCI NIH HHS / United States
R35 CA220523 / CA / NCI NIH HHS / United States
P01 HL105339 / HL / NHLBI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
P01 HL132825 / HL / NHLBI NIH HHS / United States
P50 CA165962 / CA / NCI NIH HHS / United States
P01 HL114501 / HL / NHLBI NIH HHS / United States
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