@article{3000788,
    title = "Impact of interferon-α receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma",
    author = "Karamitros, T. and Papatheodoridis, G. and Paraskevis, D. and Hatzakis, A. and Mbisa, J.L. and Georgopoulou, U. and Klenerman, P. and Magiorkinis, G.",
    journal = "Frontiers in Immunology",
    year = "2018",
    volume = "9",
    number = "APR",
    publisher = "Frontiers Media S.A",
    doi = "10.3389/fimmu.2018.00777",
    keywords = "alpha interferon receptor;  alpha interferon receptor 1;  transcriptome;  unclassified drug, Article;  bioinformatics;  clinical article;  controlled study;  down regulation;  gene expression;  gene frequency;  gene ontology;  genetic polymorphism;  genotype;  hepatitis B;  human;  liver cell carcinoma;  Pi3K/Akt signaling;  promoter region;  RNA sequence;  signal transduction;  single nucleotide polymorphism;  transcriptomics;  upregulation;  whole exome sequencing",
    abstract = "Background and aims: Genetic polymorphisms within the promoter of interferon-α receptor type-1 (IFNAR1) have been associated with the susceptibility to and the outcome of chronic hepatitis B virus (HBV) infection. However, the impact of these polymorphisms in the transcriptome of the HBV-associated hepatocellular carcinoma (HCC) remains largely unexplored. Methods: Using whole-genome and exome sequencing data from The Cancer Genome Atlas project, we characterized three single-nucleotide polymorphisms (SNPs: -568G/C, -408C/T, -3C/T) and one variable number tandem repeat [VNTR: -77(GT)n] within the IFNAR1 promoter sequence in 49 HCC patients. RNAseq data from 10 genotyped HCC samples were grouped according to their -77VNTR or -3SNP genotype to evaluate the impact of these polymorphisms on the differential expression on the HCC transcriptome. Results: There is a fourfold higher impact of the -77VNTR on the HCC transcriptome compared to the -3SNP (q < 0.1, p < 0.001). The expression of the primary IFNAR1 transcript is not affected by these polymorphisms but a secondary, HCC-specific transcript is expressed only in homozygous -77VNTR ≤8/≤8(GT)n samples (p < 0.05). At the same time, patients carrying at least one -77VNTR > 8(GT) allele, presented a strong upregulation of the fibronectin-1 (FN-1) gene, which has been associated with the development of HCC. Gene Ontology and pathway enrichment analysis of the differentially expressed genes revealed a strong disruption of the PI3K-AKT signaling pathway, which can be partially triggered by the extracellular matrix FN-1. Conclusion: The IFNAR-1 promoter polymorphisms are not involved in the expression levels of the main IFNAR-1 transcript. The -77VNTR has a regulatory role on the expression of a secondary, truncated, HCC-specific transcript, which in turn coincides with disruptions in cancer-associated pathways and in FN-1 expression modifications. © 2018 Karamitros, Papatheodoridis, Paraskevis, Hatzakis, Mbisa, Georgopoulou, Klenerman and Magiorkinis."
}