Sex differences play an important role in development and progression of many diseases, and understanding how a disease differs between the sexes is essential for the advancement of prevention, diagnosis, and treatment. For most cancer types, males have a higher risk of developing the disease and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood, and most current approaches to clinical management, as well as therapeutics development and selection, are sex-independent. We developed a sex-specific gene regulatory network approach to integrate genomic data and model gene regulation in males and females. We demonstrated that a repertoire of transcription factors drives sex-biased gene regulation, and that differentially regulated genes are enriched for tissue-related functions and diseases with sex-biased manifestations. In colon cancer, we found strong sex-biased regulation of the drug metabolism pathway, which was associated with higher survival outcomes in women treated with chemotherapy. Our findings uncovered patterns of gene regulation that differentiate males and females and may provide functional basis to explain sex differences in clinical observation. Our sex-specific regulatory network approach can be used to understand how sex influences progression and therapeutic responses in cancer and other complex diseases and may help accelerate the development and implementation of sex-specific precision medicine.

Learning Objectives:

1. Discuss conceptual and methodological gaps to incorporating sex in genomics research.

2. Discuss how sex differences in disease arise due to a combination of environmental, genetics, epigenetics, and transcriptional regulation.

3. Explain how integrative network analyses help in understanding the interplay of sex and genomics in diseases.