@article {20346,
	title = {Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma},
	journal = {Front ImmunolFront ImmunolFront Immunol},
	volume = {9},
	year = {2018},
	note = {1664-3224Karamitros, TimokratisPapatheodoridis, GeorgeParaskevis, DimitriosHatzakis, AngelosMbisa, Jean LGeorgopoulou, UraniaKlenerman, PaulMagiorkinis, GkikasMR/K010565/1/Medical Research Council/United KingdomJournal ArticleResearch Support, Non-U.S. Gov{\textquoteright}tFront Immunol. 2018 Apr 16;9:777. doi: 10.3389/fimmu.2018.00777. eCollection 2018.},
	pages = {777},
	edition = {2018/05/02},
	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.},
	keywords = {*hepatitis virus B, *hepatocellular carcinoma, *interferon-α receptor, *interferon-α receptor type-1 promoter, *polymorphism, *RNAseq, *the Cancer Genome Atlas project, *transcriptome, Carcinoma, Hepatocellular/*genetics/virology, Fibronectins/biosynthesis, Gene Expression Regulation/genetics, Genetic Predisposition to Disease/genetics, Genotype, Hepatitis B, Chronic/complications, Hepatitis B/complications, Humans, Liver Neoplasms/*genetics/virology, Polymorphism, Single Nucleotide, Promoter Regions, Genetic/genetics, Receptor, Interferon alpha-beta/*genetics, Transcriptome},
	isbn = {1664-3224 (Print)1664-3224},
	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}
}
