Sex-specific regulatory functions may underlie sex differences in cancer etiology, progression, and outcome. We detected sex differences in the germline genetic regulation of tumor gene expression in HCC, including 24 genes that were under germline regulatory control only in male HCC (Fig.
3). Functional annotations of these male-specific eGenes provide insight into possible regulatory mechanisms contributing to the observed male-bias in HCC and sex differences in HCC etiology. Protein O-glucosyltransferase 1 (
POGLUT1) was found to be under germline regulation in male HCC, but not in female HCC nor in the joint analysis of both sexes (Fig.
3d). The eQTL associated with
POGLUT1 is located on a promoter region of its target (Additional file
3: Table S15).
POGLUT1 is an enzyme that is responsible for O-linked glycosylation of proteins. Altered glycosylation of proteins has been observed in many cancers [
52,
53], including liver cancer [
54,
55].
POGLUT1 is an essential regulator of Notch signaling and is likely involved in cell fate and tissue formation during development. Genes involved in Notch and PI3K/AKT signaling were also found to be expressed in a sex-biased way in HCC tumors and overrepresented among the male-specific DEGs detected in the tumor vs. tumor-adjacent comparison, showing that sex-specific eQTLs and sex-specific dysregulated genes converge in canonical pathways. Notch signaling pathway was also detected as overrepresented (FDR-adj.
p-value ≤0.01) among the 24 male-specific eGenes. PI3K-AKT is known to co-operate with Notch by triggering inflammation and immunosuppression [
56]. Concurrent activation of Notch and PI3K/AKT pathways can trigger tumorigenesis and is prevalent in aggressive cancers [
57‐
60]. We find simultaneous activation of PI3K/AKT and Notch pathways in male HCC, and sex-specific genetic effects on regulation of genes involved in PI3K/AKT signaling. These results point to a major role of the Notch/PI3K/AKT axis in the development of HCC in males. PI3K/AKT signaling is of particular interest in the context of HCC, as it has been implicated in HCC carcinogenesis [
61], is involved in hepatic gluconeogenesis [
62], and is activated in a sex-biased way in the liver and other tissues [
63]. The role of Notch and PI3K/AKT signaling in HCC may differ between early and late-stage tumors and among molecular subtypes, and further studies are necessary to understand the oncogenic properties of these pathways among HCC subtypes and between the sexes. In the future, analyses of data collected as a part of the International Cancer Genomics Consortium project may elucidate the sex-specific processes of HCC oncogenesis among the Japanese, as well as the interactions between sex and hepatitis infections in shaping HCC etiology. However, each dataset has a unique ancestry composition and are not directly comparable for validation purposes.