Impact of interferon-α receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma

Timokratis Karamitros*, George Papatheodoridis, Dimitrios Paraskevis, Angelos Hatzakis, Jean L. Mbisa, Urania Georgopoulou, Paul Klenerman, Gkikas Magiorkinis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article number777
JournalFrontiers in Immunology
Volume9
Issue numberAPR
DOIs
Publication statusPublished - 16 Apr 2018

Bibliographical note

Funding Information:
The work was supported the Medical Research Council, UK (Project Reference: MR/K010565/1).

Publisher Copyright:
© 2018 Karamitros, Papatheodoridis, Paraskevis, Hatzakis, Mbisa, Georgopoulou, Klenerman and Magiorkinis.

Keywords

  • Hepatitis virus B
  • Hepatocellular carcinoma
  • Interferon-α receptor
  • Interferon-α receptor type-1 promoter
  • Polymorphism
  • RNAseq
  • The Cancer Genome Atlas project
  • Transcriptome

Fingerprint

Dive into the research topics of 'Impact of interferon-α receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma'. Together they form a unique fingerprint.

Cite this