Tumor transcriptome analysis and immune infiltrate profiling suggests a role for the IFNL3/IFNL4 genomic locus in liver cancer

Abstract

Abstract HCV infection and cirrhosis are among the strongest risk factors for developing liver cancer. Impaired HCV clearance is strongly associated with a dG allele of a genetic variant, rs368234815-TT/dG; this allele creates an open reading frame for interferon lambda 4 (IFNL4). The dG allele has also been linked to reduced risk of cirrhosis. Despite strong association of HCV and cirrhosis with liver cancer, no link between rs368234815-TT/dG and liver cancer has been reported. To evaluate potential association of rs368234815-TT/dG with liver cancer, we explored resources of The Cancer Genome Atlas (TCGA). We used a genetic variant rs12980275-A/G located downstream of IFNL3 gene as a TCGA-genotyped proxy for rs368234815-TT/dG. Using multivariate statistical models, we observed that liver cancer patients homozygous for rs12980275-G allele (corresponds to rs368234815-dG allele) had less cirrhosis but reduced survival. Tumor transcriptome analysis showed association of rs12980275-G allele with immunosuppressed tumor microenvironment in non-cirrhotic patients. By deconvoluting tumor infiltrating immune cell signatures, we observed lower levels of CD8+ and follicular helper T cells, but increased M1 macrophages in non-cirrhotic patients with rs12980275-G allele. Transcriptome analysis also identified metallothioneins (MTs), which are involved in removal of reactive oxygen species in the liver, to be differentially expressed according to rs12980275 genotypes. Using hepatoma cell lines, we show that MTs are induced by IFNL4. Our results suggest an association of IFNL3/IFNL4 locus with both an immunosuppressed tumor microenvironment in liver cancer, and increased expression of MTs which could contribute to reduced fibrosis.