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.

Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update

“…Although HLA alleles have been studied in the context of specific responses to HIV and other pathogens, there are currently no specific diseases or conditions that have been strongly linked to HLA‐B*15:02 or HLA‐A*31:01 independent of drug use . However, HLA‐B*15:02 has also been associated with SJS/TEN from phenytoin use, and other HLA‐B alleles have been strongly associated with adverse drug reactions.…”

“…Although HLA alleles have been studied in the context of specific responses to HIV and other pathogens, there are currently no specific diseases or conditions that have been strongly linked to HLA-B*15:02 or HLA-A*31:01 independent of drug use. [3][4][5] However, HLA-B*15:02 has also been associated with SJS/TEN from phenytoin use, and other HLA-B alleles have been strongly associated with adverse drug reactions. For example, HLA-B*57:01 is associated with abacavir-induced hypersensitivity reaction, and HLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse reactions (including SJS/TEN and DRESS).…”

Prevalence of Human Papillomavirus in Women from the State of Michoacan, Mexico, Showed High Frequency of Unusual Virus Genotypes

“…This may be related to the major histocompatibility complex (MHC) [27][28][29] and health of the patient, the homeostasis of the immune system, or the historical evolution of the infection, which we did not explore in this study.…”

The effect of aberrant expression and genetic polymorphisms of Rad21 on cervical cancer biology

“…Persistent infection of high‐risk HPV has been considered as a main cause of CC. Genetic factors such as gene SNPs may participate in the malignant transformation of HPV‐infected cells to CC onset . SNP changes also have the potential to predict clinical responses to chemoradiotherapy and the disease progression of CC …”

“…Genetic factors such as gene SNPs may participate in the malignant transformation of HPV-infected cells to CC onset. 2 SNP changes also have the potential to predict clinical responses to chemoradiotherapy and the disease progression of CC. 3 The ring-shaped cohesin complex plays an important role in many aspects of chromosome biology, including sister chromatid cohesion, DNA repair, and transcriptional regulation.…”