No Association between Endogenous Retinoic Acid and Human Papillomavirus Clearance or Incident Cervical Lesions in Brazilian Women

Abstract

Although oncogenic human papillomavirus (HPV) infections have been established as the necessary cause of cervical cancer, most HPV infections are transient and rarely progress to squamous cervical lesions. The activity of HPV is tightly associated with epithelial cell differentiation; therefore, regulators of differentiation, such as retinoic acid (RA), have been considered targets for the prevention of HPV-associated squamous intraepithelial lesion (SIL) development. The purpose of this study was to determine the association between circulating RA and early events in cervical carcinogenesis, specifically type-specific HPV clearance and SIL detection. Archived blood samples from 643 women participating in the Ludwig-McGill Cohort in São Paulo, Brazil, were analyzed by high-pressure liquid chromatography for three RA isomers (all-trans, 13-cis, and 9-cis-RA). A type-specific HPV clearance event was defined as two consecutive visits negative for an HPV type during follow-up for 364 HPV-positive women. Among the 643 women in this analysis, 78 were diagnosed with incident SIL. The probability of clearing an oncogenic HPV infection was not significantly different across RA isomer quartiles. There was a suggestion that increasing all-trans-RA increased the rate of nononcogenic HPV clearance (P-trend = 0.05). There was no association observed between serum RA levels and incident SIL. Our results suggest that elevated circulating RA isomer levels do not increase the rate of HPV clearance or reduce the risk of incident SIL. The role of RA in the inhibition of HPV-induced carcinogenesis, as shown in vitro, lacks confirmatory evidence within epidemiologic studies among women.