Human Papillomavirus-16 and 18 in Penile Carcinomas: DNA Methylation Chromosomal Recombination and Genomic Variation

摘要

Penile carcinomas are frequently associated with high-risk human papillomavirus (HPV) types. Since little is known about the molecular biology of this association, we investigated three properties of HPV genomes in penile carcinomas from Brazilian patients: (i) HPV DNA methylation, (ii) junctions between HPV and cellular DNA, and (iii) genomic variation. In cervical carcinogenesis, recombination between HPV and chromosomal DNA is frequent and likely necessary for progression, and DNA hypermethylation - specifically of the L1 gene - is a biomarker for cancerous progression. The same mechanisms apparently occur during penile carcinogenesis, because 95 HPV-16 molecules derived from 19 penile lesions had 58% of the CpGs in L1 and 22% in the 5′ part of the long control region methylated, more than the percentages found in cervical carcinomas. In addition, two out of three HPV-18 infections, all present in double-infections with HPV-16, showed L1 specific methylation typical of malignant cervical lesions. In 11 out of 15 HPV-16 lesions we confirmed chromosomal integration by reverse ligation inverted PCR, while four samples had concatemeric integrations or episomes. Nine of 17 penile carcinomas contained HPV-16 AA variants, and eight E variants. As AA variants are relatively rare in Brazilian cohorts of asymptomatic women, the high prevalence in penile carcinomas may indicate a higher risk of progression of AA lesions, as suspected for cervical infections. Our observations of frequent viral DNA methylation, chromosomal integration, and the prevalence of high-risk variants suggest that HPV dependent carcinogenesis of the penis and cervix follow similar etiological and epidemiological parameters.