Abstract 396: Sex-specific genomic architecture and regulatory mechanisms underlying hepatocellular carcinoma
Authors: Natri Heini M. , Sayres Melissa Wilson , Buetow Kenneth 
Published: August 2018

The occurrence and mortality rates of most types of cancer are significantly higher in males than in females. Environmental risk factors may explain some portion of the sex-bias, but cellular and molecular differences are also likely important. The sexes differ in their endocrinological and immunological functions, genetic makeup, and in their response to some forms of chemotherapy and immunotherapy. However, sex differences are rarely considered in the development of cancer therapies. Targeted approaches to the treatment of male and female tumors will require characterizing and understanding the fundamental biological mechanisms that differentiate them.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. HCC is influenced by genetic susceptibility, environmental factors such as oncogenic viral infections, metabolic syndrome, and alcohol use, and shaped by numerous biological processes, resulting in a high degree of genetic and transcriptional heterogeneity. HCC incidence in the US has doubled in the last 3 decades, attributable to increased rates of obesity. HCC exhibits sex bias in occurrence with 2.1-fold higher rate in HBV+ males, 1.9-fold in HCV+ females.

While sex-bias in HCC is partly attributed to sex-specific differences in risk behaviors and environmental exposure, the relationship of these factors and sex as a biological variable has not been systematically investigated. Moreover, most GWAS and eQTL studies as yet have failed to explore the role of sex-specific impacts of regulatory variants.

Here, we utilize an integrative systems genetic approach to investigate the mechanisms involved in HCC. By sex-specific analyses of genotypic, transcriptomic, and phenotypic data from GTEx, TCGA, and ICGC datasets, we have produced a detailed characterization of regulatory networks underlying HCC occurrence and susceptibility. As mis-mapping of sequence reads along the sex chromosomes may increase the rate of false negatives when accounting for sex-biased gene expression, we have utilized custom sex-specific reference genome sequence alignments. We have carried out gene and isoform level analyses of differential expression, pathway enrichment analyses, cis- and trans-eQTL mapping, and de novo network analyses to identify the mechanisms underlying HCC oncogenesis in each sex. Substantial sex-biased gene expression was detected in normal liver tissue, as well as tumor-adjacent and tumor tissues. Analyses of paired tumor and tumor-adjacent samples imply that distinct oncogenic pathways shape HCC in males and females. We found considerable differences in significant eQTLs between sexes. Constructed networks further elucidate the sex-specific regulatory mechanisms of HCC oncogenesis. Our results illustrate the highly sex-dependent genomic architecture of HCC, with implications for future studies and targeted therapies.

Citation Format: Heini M. Natri, Melissa Wilson Sayres, Kenneth Buetow. Sex-specific genomic architecture and regulatory mechanisms underlying hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 396.