Impact of genetic variations and transcriptional alterations of HLA class I genes on cervical cancer pathogenesis.

Autor: Das Ghosh D; Human Genetics Unit, Indian Statistical Institute, Kolkata, India., Mukhopadhyay I; Human Genetics Unit, Indian Statistical Institute, Kolkata, India., Bhattacharya A; Cancer Genomics and Epigenomics, National Institute of Biomedical Genomics, Netaji Subhas Sanatorium, Kalyani, West Bengal, India., Roy Chowdhury R; Department of Gynecology, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India., Mandal NR; Department of Gynecology, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India., Roy S; Department of Pathology, Sri Aurobindo Seva Kendra, Kolkata, West Bengal, India., Sengupta S; Cancer Genomics and Epigenomics, National Institute of Biomedical Genomics, Netaji Subhas Sanatorium, Kalyani, West Bengal, India.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2017 Jun 01; Vol. 140 (11), pp. 2498-2508. Date of Electronic Publication: 2017 Mar 24.
DOI: 10.1002/ijc.30681
Abstrakt: In a novel attempt to understand the variations in DNA sequences underlying HLA class I alleles associated with HPV16-related CaCx, we determined the alleles by reconstructing SNP-based haplotypes from resequencing of the most polymorphic exons 2 and 3 of HLA-A, HLA-B and HLA-C. We also determined the impact of SNPs and transcriptional alterations of the genes on CaCx. A high density of SNPs was identified from resequencing. HLA expression was determined by real-time PCR. We identified that even a single associated HLA allele had many underlying SNP-based haplotypes. Out of the most frequent (≥5%) HLA class I alleles, HLA-B*40:06 and HLA-B*15:02 respectively imparted significant risk towards and protection from CaCx as well as HPV16 infection. Employing median-joining networks to detect clusters of sequence-variations for specific HLA alleles, we found the protective SNP-based signature, GAATTTA, in all SNP-based haplotypes of HLA-B*15:02 allele. The signature was derived from seven SNPs within HLA-B which were newly associated with the disease. Contrarily, similarly derived risk-signature, TTGCGCC, mapped only to 52% of SNP-based haplotypes of HLA-B*40:06 allele. This indicated that all SNP-based haplotypes underlying a particular associated HLA allele might or might not have a single signature of risk/protection. HLA-A, HLA-B and HLA-C expressions were downregulated among CaCx cases compared to asymptomatic infections and HPV-negative controls. HLA-A and HLA-B were repressed in both cases harbouring episomal and integrated HPV16, whereas HLA-C in only the latter. Novel genetic variations and differential downregulation-patterns of HLA class I have a significant bearing on HPV16-related CaCx pathogenesis.
(© 2017 UICC.)
Databáze: MEDLINE
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