Sex differences in gene regulation and its impact on cancer incidence.

There are significant sex differences in cancer incidence, yet the underlying regulatory mechanisms in normal tissues remain poorly understood. We studied 8,279 gene regulatory networks across 29 non-cancerous tissues and compared network centrality by sex. Cancer genes were differentially targeted by transcription factors in males and females, with an overrepresentation on the X chromosome, particularly among X-inactivation escapees, and key signaling pathways such as WNT, NOTCH, and p53. We observed higher targeting of cancer-related pathways in females for tissues that have higher tumor incidence in females (breast, lung, and thyroid) and higher targeting in males for tissues with increased tumor incidence in males (stomach, colon, and liver), a pattern replicated in independent lung data. Sex-biased transcription factors were enriched for sex hormone response elements. These findings suggest that sex-biased transcriptional programs in normal tissues contribute to sex differences in cancer incidence and should be considered in cancer prevention strategies.