Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2018 May 2

PMID 29713327

Citations 6

Authors

Timokratis Karamitros

George Papatheodoridis

Dimitrios Paraskevis

Angelos Hatzakis

Jean L Mbisa

Urania Georgopoulou

Paul Klenerman

Gkikas Magiorkinis

Affiliations

Soon will be listed here.

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 ( < 0.1, < 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 ( < 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.

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