Loss of heterozygosity on chromosome 6 in HPV‐16 positive cervical carcinomas carrying the DRB1*1501‐DQB1*0602 haplotype

Abstract

High-risk human papillomaviruses (HPVs), specifically HPV-16 and -18, have been associated with the development of carcinoma in situ (CIS) and of invasive cervical cancer (CC). However, only a small fraction of HPV-infected women will show signs of disease progression, suggesting that other factors in the carcinogenic pathway are needed. We previously demonstrated that human leukocyte antigen (HLA) DRB1*1501-DQB1*0602 (high risk) was associated with the development of CIS and CC tumors in HPV-16-positive patients. To characterize the molecular changes that could be relevant to tumor progression, we compared the extent of loss of heterozygosity (LOH) on chromosome 6 in HPV-16-positive CIS patients who were carriers of high-risk and neutral HLA haplotypes. CIS and CC cases demonstrated similar LOH patterns. A wide range of LOH frequencies was found at 6p (10-53%) and 6q (5-28%) in CIS cases, suggesting that LOH is an early event in the carcinogenic process. A comparative analysis of LOH frequencies in the high-risk versus the neutral HLA haplotypes showed a statistically significant difference in the extent of LOH at 6p24-p25 (58.6% versus 25.8%; P = 0.018) and at 6p21.3 (79.3% versus 35.5%; P = 0.001), a region that contains the HLA complex. LOH at this region could affect genes encoding HLA class I-II molecules, as well as factors responsible for the assembly, transport, and stable expression of HLA molecules. These losses may be a reflection of both an abnormal immune response and a general genome-wide instability resulting from virus persistence.

Risks for Persistence and Progression by Human Papillomavirus Type 16 Variant Lineages Among a Population-Based Sample of Danish Women

“…It is possible that HPV16 variants in concert with HLA (34) and other immune-genetic polymorphisms play a role in persistence. For instance, diverse HLA and killer immunoglobulin-like receptor combinations (35) or gene polymorphisms within noncoding regions of cytokine genes could confer susceptibility or be protective to cervical neoplasia development. Furthermore, the polymorphism at position 350 in E6 could be linked phylogenetically to one or more other parts of the HPV16 genome that are accounting for part, or even all, of the observed differences.…”

Human Papillomavirus Type 16 Integration in Cervical Carcinoma In Situ and in Invasive Cervical Cancer

“…Tumor cells from paraffin-embedded tissue specimens were microdissected as described by Arias-Pulido et al (1). Briefly, cells were isolated by manual microdissection after toluidine blue staining (0.05% [wt/vol]), and normal and tumor DNA from each individual specimen was crudely extracted by digestion with proteinase K (10 mM Tris, 1 mM EDTA [pH 8.5], proteinase K, 0.2 mg/ml, 0.1% Laureth-12) for 24 h at 55°C, followed by proteinase K inactivation at 95°C for 10 min.…”

Polymorphic amino acids at codons 9 and 37 of HLA‐DQB1 alleles may confer susceptibility to cervical cancer among Chinese women

“…2 Infections are common but only a small fraction progresses into persistent infection and cancer, suggesting that other factors are needed for the pathogenesis. 3 One potential cofactor may be the host cellular immune response to HPV infection, mediated by HLA-restricted T lymphocytes. To date, there are more than 100 different HPV genotypes.…”