Impact of interferon-alpha receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma
<p><b>Background and aims:</b> 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 transcr...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Journal article |
| Published: |
Frontiers Media
2018
|
| _version_ | 1797086726582173696 |
|---|---|
| author | Karamitros, T Papatheodoridis, G Paraskevis, D Hatzakis, A Mbisa, J Georgopoulou, U Klenerman, P Magiorkinis, G |
| author_facet | Karamitros, T Papatheodoridis, G Paraskevis, D Hatzakis, A Mbisa, J Georgopoulou, U Klenerman, P Magiorkinis, G |
| author_sort | Karamitros, T |
| collection | OXFORD |
| description | <p><b>Background and aims:</b> 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. </p><p><b>Methods:</b> 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. </p><p><b>Results:</b> 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. </p><p><b>Conclusion:</b> 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.</p> |
| first_indexed | 2024-03-07T02:26:04Z |
| format | Journal article |
| id | oxford-uuid:a5a80635-886b-4040-bbb2-9db14e3f43d0 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T02:26:04Z |
| publishDate | 2018 |
| publisher | Frontiers Media |
| record_format | dspace |
| spelling | oxford-uuid:a5a80635-886b-4040-bbb2-9db14e3f43d02022-03-27T02:41:48ZImpact of interferon-alpha receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinomaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a5a80635-886b-4040-bbb2-9db14e3f43d0Symplectic Elements at OxfordFrontiers Media2018Karamitros, TPapatheodoridis, GParaskevis, DHatzakis, AMbisa, JGeorgopoulou, UKlenerman, PMagiorkinis, G <p><b>Background and aims:</b> 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. </p><p><b>Methods:</b> 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. </p><p><b>Results:</b> 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. </p><p><b>Conclusion:</b> 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.</p> |
| spellingShingle | Karamitros, T Papatheodoridis, G Paraskevis, D Hatzakis, A Mbisa, J Georgopoulou, U Klenerman, P Magiorkinis, G Impact of interferon-alpha receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma |
| title | Impact of interferon-alpha receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma |
| title_full | Impact of interferon-alpha receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma |
| title_fullStr | Impact of interferon-alpha receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma |
| title_full_unstemmed | Impact of interferon-alpha receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma |
| title_short | Impact of interferon-alpha receptor-1 promoter polymorphisms on the transcriptome of the hepatitis B virus-associated hepatocellular carcinoma |
| title_sort | impact of interferon alpha receptor 1 promoter polymorphisms on the transcriptome of the hepatitis b virus associated hepatocellular carcinoma |
| work_keys_str_mv | AT karamitrost impactofinterferonalphareceptor1promoterpolymorphismsonthetranscriptomeofthehepatitisbvirusassociatedhepatocellularcarcinoma AT papatheodoridisg impactofinterferonalphareceptor1promoterpolymorphismsonthetranscriptomeofthehepatitisbvirusassociatedhepatocellularcarcinoma AT paraskevisd impactofinterferonalphareceptor1promoterpolymorphismsonthetranscriptomeofthehepatitisbvirusassociatedhepatocellularcarcinoma AT hatzakisa impactofinterferonalphareceptor1promoterpolymorphismsonthetranscriptomeofthehepatitisbvirusassociatedhepatocellularcarcinoma AT mbisaj impactofinterferonalphareceptor1promoterpolymorphismsonthetranscriptomeofthehepatitisbvirusassociatedhepatocellularcarcinoma AT georgopoulouu impactofinterferonalphareceptor1promoterpolymorphismsonthetranscriptomeofthehepatitisbvirusassociatedhepatocellularcarcinoma AT klenermanp impactofinterferonalphareceptor1promoterpolymorphismsonthetranscriptomeofthehepatitisbvirusassociatedhepatocellularcarcinoma AT magiorkinisg impactofinterferonalphareceptor1promoterpolymorphismsonthetranscriptomeofthehepatitisbvirusassociatedhepatocellularcarcinoma |