Abstract
Sex differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality. Most HCC studies, to date, have failed to explore the sex-specific effects in gene regulatory functions. Here we have characterized the regulatory functions underlying HCC tumors in sex-stratified and combined analyses. By sex-specific analyses of differential expression of tumor and tumor adjacent samples, we uncovered etiologically relevant genes, pathways and canonical networks differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and p53 signaling, pathways involved in innate and adaptive immunity showed differential activation between the sexes. Using eQTL analyses, we discovered germline regulatory variants with differential effects on tumor gene expression between the sexes. We discovered eQTLs overlapping HCC GWAS loci, providing regulatory mechanisms connecting these loci to HCC risk. Furthermore, we discovered genes under germline regulatory control that alter survival in patients with HCC, including some that exhibited differential effects on survival between the sexes. Overall, our results provide new insight into the role of genetic regulation of transcription in modulating sex differences in HCC occurrence and outcome and provide a framework for future studies on sex-biased cancers.
Author Summary Sex differences in cancer occurrence and mortality are evident across tumor types, and targeted approaches to the treatment male and female tumors require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality. Here, we have characterized the regulatory functions underlying male and female HCC. We show that while HCC shares commonalities across the sexes, it shows demonstrable regulatory differences that could be critical in terms of prevention and treatment: we detected differential activation of pathways involved in innate and adaptive immunity, as well as differential genetic effects on gene expression, between the sexes. Furthermore, we have detected regulatory variants overlapping known HCC GWAS risk loci, providing regulatory mechanisms connecting these risk variants to HCC. Finally, we discovered genes under germline regulatory control altering the overall survival of patients with HCC, including some that showed differential effects between the sexes. Overall, our findings create a paradigm for future studies on sex-biased cancers.
