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Cancer Res. 2018 Oct 1;78(19):5538-5547. doi: 10.1158/0008-5472.CAN-18-0454.

Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism.

Lopes-Ramos CM1,2, Kuijjer ML1,2, Ogino S3,4,5,6, Fuchs CS7,8,9, DeMeo DL10,11, Glass K10, Quackenbush J12,2,13.

Author information

1
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
3
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
4
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
5
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
7
Yale Cancer Center, New Haven, Connecticut.
8
Department of Medicine, Yale School of Medicine, New Haven, Connecticut.
9
Smilow Cancer Hospital, New Haven, Connecticut.
10
Channing Division of Network Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
11
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
12
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. johnq@hsph.harvard.edu.
13
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

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 (P = 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.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 understand how sex influences progression and response to therapies in other cancers. Cancer Res; 78(19); 5538-47. ©2018 AACR.

PMID:
30275053
PMCID:
PMC6169995
[Available on 2019-10-01]
DOI:
10.1158/0008-5472.CAN-18-0454

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