Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas

To investigate if viral load, integration and methylation of E2BS3 and 4 represent different ways of tumor transformation in vaginal and vulvar carcinoma and to elucidate its clinical impact. Fifty-seven samples, positive for HPV16, were selected for the study. Detection of viral load was made with...

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Vydáno v:	PloS one Ročník 9; číslo 11; s. e112839
Hlavní autoři:	Lillsunde Larsson, Gabriella, Helenius, Gisela, Sorbe, Bengt, Karlsson, Mats G.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 2014 Public Library of Science (PLoS)
Témata:	Antiretroviral drugs Biology and Life Sciences Biomarkers Carcinogenesis Carcinogens Carcinoma Cell cycle Cervical cancer Copy number Deoxyribonucleic acid DNA DNA methylation DNA, Viral - metabolism Female Gene expression Genital cancers Genomes Genotype & phenotype Hospitals Human papillomavirus Human papillomavirus 16 - metabolism Humans Integration Laboratories Medicine and Health Sciences Methylation Papillomavirus Infections - metabolism Papillomavirus Infections - mortality Papillomavirus Infections - pathology Pathogenesis Polymerase chain reaction Proteins Retrospective Studies Sampling methods Studies Survival Transformation Tumors Vagina Vaginal Neoplasms - metabolism Vaginal Neoplasms - mortality Vaginal Neoplasms - pathology Vaginal Neoplasms - virology Viral Load Virus Integration Viruses Vulvar Neoplasms - metabolism Vulvar Neoplasms - mortality Vulvar Neoplasms - pathology Vulvar Neoplasms - virology Sweden
ISSN:	1932-6203, 1932-6203
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Shrnutí:	To investigate if viral load, integration and methylation of E2BS3 and 4 represent different ways of tumor transformation in vaginal and vulvar carcinoma and to elucidate its clinical impact. Fifty-seven samples, positive for HPV16, were selected for the study. Detection of viral load was made with realtime-PCR using copy numbers of E6 and integration was calculated from comparing E2 to E6-copies. Methylation of E2BS3 and 4 was analysed using bisulphite treatment of tumor DNA, followed by PCR and pyrosequencing. Vaginal tumors were found to have a higher viral load (p = 0.024) compared to vulvar tumors but a high copy number (> median value, 15,000) as well as high methylation (>50%) was significantly (p = 0.010 and p = 0.045) associated with a worse cancer-specific survival rate in vulvar carcinoma, but not in vaginal carcinoma. Four groups could be defined for the complete series using a Cluster Two step analysis; (1) tumors holding episomal viral DNA, viral load below 150,000 copies not highly methylated (n = 25, 46.3%); (2) tumors harboring episomal viral DNA and being highly methylated (>50%; n = 6, 11.1%); (3) tumors with viral DNA fully integrated (n = 11, 20.4%), and (4) tumors harboring episomal viral DNA and being medium- or unmethylated (<50%) and having a high viral load (> total mean value 150,000; n = 12, 22.2%). The completely integrated tumors were found to be distinct group, whilst some overlap between the groups with high methylation and high viral load was observed. HPV16- related integration, methylation in E2BS3 and 4 and viral load may represent different viral characteristics driving vaginal and vulvar carcinogenesis. HPV16- related parameters were found to be of clinical importance in the vulvar series only.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: GLL GH MK. Performed the experiments: GLL. Analyzed the data: GLL BS. Contributed reagents/materials/analysis tools: GLL GH MK BS. Contributed to the writing of the manuscript: GLL GH MK BS. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0112839