Human leukocyte antigen class II DRB1*1302 allele protects against cervical cancer: At which step of multistage carcinogenesis?

We investigated the role of human leukocyte antigen (HLA) class II alleles in multistage cervical carcinogenesis. Cross-sectional analysis for HLA association with cervical cancer included 1253 Japanese women: normal cytology (NL, n = 341), cervical intraepithelial neoplasia grade 1 (CIN1, n = 505), CIN grade 2 or 3 (CIN2/3, n = 96), or invasive cervical cancer (ICC, n = 311). The HLA class II allele frequencies were compared by Fisher's exact test or the χ(2) -test. The Bonferroni adjustment corrected for multiple comparisons. Among the study subjects, 454 women with low-grade squamous intraepithelial lesion cytology were prospectively monitored by cytology and colposcopy every 3-4 months to analyze cumulative risk of CIN3 within the next 10 years in relation to HLA class II alleles. HLA class II DRB1*1302 allele frequency was similar between women with NL (11.7%) and CIN1 (11.9%), but significantly decreased to 5.2% for CIN2/3 and 5.8% for ICC (P = 0.0003). Correction for multiple testing did not change this finding. In women with low-grade squamous intraepithelial lesion cytology, the cumulative risk of CIN3 diagnosed within 10 years was significantly reduced among DRB1*1302-positive women (3.2% vs. 23.7%, P = 0.03). In conclusion, the two different types of analysis in this single study showed the protective effect of the DRB1*1302 allele against progression from CIN1 to CIN2/3.

HLA class II DRB1*1302 allele protects against progression to cervical intraepithelial neoplasia grade 3: a multicenter prospective cohort study.

OBJECTIVE: Genetic variations in human leukocyte antigens (HLA) class II regions may influence the risk of cervical cancer by altering the efficiency of the immune responses to human papillomavirus antigens. This prospective study was designed to evaluate the effects of HLA class II alleles on the natural course of cervical precursor lesions. METHODS: We followed a total of 454 Japanese women with cytological low-grade squamous intraepithelial lesion (LSIL) and histological cervical intraepithelial neoplasia grades 1 to 2 (CIN1-CIN2). Patients were tested for HLA class II alleles and cervical human papillomavirus DNA at the time of entry and then monitored by cytology and colposcopy every 4 months for a mean follow-up of 39.0 months. We analyzed cumulative probabilities of cytological regression to at least 2 consecutive negative Papanicolaou tests and histological progression to biopsy-positive CIN3. RESULTS: During the follow-up period, 39 lesions progressed to CIN3, and 282 lesions regressed to normal cytology. Progression to CIN3 did not occur in DRB1*1302-positive women, and this protective effect of DRB1*1302 was statistically significant (P = 0.03). Low-grade squamous intraepithelial lesion regressed to normal cytology more quickly in DRB1*1302-positive women than in DRB1*1302-negative women (median time, 8.9 months vs 14.2 months), although the difference was not statistically significant (P = 0.16). The risk of LSIL persistence or progression to CIN3 within 5 years was not affected by any other HLA class II alleles. CONCLUSION: By using a prospective study design, we demonstrated the protective effect of the DRB1*1302 allele against progression to CIN3 among Japanese women with LSIL.

Analysis of HLA-DRB1*0901-binding HPV-16 E7 helper T cell epitope.

AIM: This study sought to determine the human papillomavirus (HPV)-16 E7 epitopes that would be presented by HLA-DR molecules to CD4-positive T cells in patients with cervical carcinoma. METHODS: HLA-DR binding assays were performed using HPV-16 E7-derived synthetic peptides and, after incubation with these DR-binding peptides, helper T cell frequencies were analyzed in patients whose HLA and HPV genotypes were confirmed. RESULTS: We determined that the E7d peptide, 61CDSTLRLCVQSTHVDIRTL80E, was bound by HLA-DRB1*0901. An increased frequency (0.3-2.4%) of type 2 helper T cell responses was found in HLA-DRB1*0901-positive patients with cervical dysplasia and carcinoma. We found that when IL-12 was combined with E7d-peptide stimulation in vitro, the frequency of type 1 helper T cell responses also increased in patients with carcinoma. CONCLUSION: Thus HPV-16 E7d peptide as an HLA-DRB1*0901-restricted helper T cell epitope might usefully be incorporated into an understanding of the immunological mechanism and immunotherapy for this disease.

Human papillomavirus type 16 E6 variants and HLA class II alleles among Japanese women with cervical cancer.

The enhanced oncogenicity of particular human papillomavirus type 16 (HPV16) E6 variants is population-dependent, implying the involvement of additional genetic cofactors. This study was designed to investigate the association between E6 variants and human leukocyte antigen (HLA) polymorphism within a Japanese population. Fifty-seven women with HPV16-positive cervical cancer were analyzed for E6 sequence variation and its relationship to HLA class II alleles. Compared with local controls (n = 138) and published controls (n = 916), DRB1*1501 and DQB1*0602 frequencies were significantly increased among patients with HPV16 E6 prototype (n = 11). Additionally, DRB1*1502 was positively associated with a particular E6 variant designated D25E (n = 25), although we could not find a significant association between HLA class II alleles and L83V variants (n = 16). Our observations suggest that a specific match between E6 variant proteins and HLA types may contribute to HPV16-related cervical carcinogenesis.