Case–control study of HLA-G promoter methylation status, HPV infection and cervical neoplasia in Curitiba, Brazil: a pilot analysisReport as inadecuate




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BMC Cancer

, 12:618

Genetics, genomics and epigenetics

Abstract

BackgroundThe causal association between persistent human papillomavirus HPV infection and cervical cancer has been established, but the mechanisms that favor HPV persistence in cervical cells are still unknown. The diminished capability of the immune system to control and resolve HPV infection is one of several hypotheses. The tolerogenic protein HLA-G has shown aberrant expression in a variety of cancers, which has been suggested as a mechanism for tumor escape from immunosurveillance. In the present study we evaluate the role of epigenetic modification promoter de-methylation of the HLA-G gene on susceptibility to HPV infection and development of high-grade cervical lesions.

MethodsA case–control study was carried out in Curitiba, Brazil, between February and June 2010. A total of 789 women aged 15–47 years were recruited: 510 controls with normal cervical cytology, and 279 cases with histologically confirmed cervical intraepithelial neoplasia grade 2 CIN2, N = 150 or grade 3 CIN3, N = 129. All women were administered a questionnaire by interview, which collected information on demographic and lifestyle factors, and a cervical sample was collected. HPV DNA detection was performed by GP5+-GP6+ primer-mediated PCR. HPV-positive samples were genotyped by multiplex PCR. A pilot analysis of HLA-G promoter methylation was carried out in a subset of the study population 96 cases and 76 controls by pyrosequencing. HLA-G methylation and HPV infection status of cases and controls were compared, and confounding factors were computed by t Student and non-parametric Wilcoxon tests. Comparison of HLA-G methylation between cases and controls was assessed by the Bonferroni correction. The association of HLA-G methylation with CIN2-3 was evaluated by logistic regression.

ResultsHPV prevalence was 19.6% in controls and 94.3% in CIN2-3 cases. HPV16, 31, 33, 35 and 18 were the most prevalent types. Methylation analysis of seven CpGs in the HLA-G promoter did not reveal any spontaneous de-methylation events in CIN2-3 cases mean proportion of methylation: 75.8% with respect to controls mean 73.7%; odds ratio 1.01, 95% confidence interval 0.96, 1.07.

ConclusionsThis study did not support the hypothesis that spontaneous de-methylation events in the HLA-G promoter play a primary role in promoting escape from immunosurveillance in the development of precancerous cervical lesions.

KeywordsHPV Cervical cancer HLA-G Methylation AbbreviationsCIConfidence interval

CINCervical intraepithelial neoplasia

HLA-GHuman leucocyte antigen-G

HPVHuman papillomavirus

LIGHLaboratory of Immunogenetics and Hystocompatibility

OROdds ratio.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-12-618 contains supplementary material, which is available to authorized users.

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