title: Impact of genetic variations and transcriptional alterations of HLA class I genes on cervical cancer pathogenesis.
abstract: 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.
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Damayanti
authors.initials: D
authors.lastname: Das Ghosh
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Indranil
authors.initials: I
authors.lastname: Mukhopadhyay
authors.affiliation: Cancer Genomics and Epigenomics, National Institute of Biomedical Genomics, Netaji Subhas Sanatorium, Kalyani, West Bengal, India.
authors.forename: Amrapali
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Gynecology, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Roy Chowdhury
authors.affiliation: Department of Gynecology, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India.
authors.forename: Nidhu Ranjan
authors.initials: NR
authors.lastname: Mandal
authors.affiliation: Department of Pathology, Sri Aurobindo Seva Kendra, Kolkata, West Bengal, India.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Roy
authors.affiliation: Cancer Genomics and Epigenomics, National Institute of Biomedical Genomics, Netaji Subhas Sanatorium, Kalyani, West Bengal, India.
authors.forename: Sharmila
authors.identifier: 0000-0003-2462-5198
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D005805:Genes, MHC Class I / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D052162:Human papillomavirus 16 / Q000472:pathogenicity; D006801:Humans; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000209:etiology / Q000235:genetics* / Q000821:virology
chemical_list: D015235:HLA-B Antigens; D015236:HLA-C Antigens
keywords: HLA class I alleles; HPV16; SNP; cervical cancer; differential expression