Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

Michael J Lace; James R Anson; Jens P Klussmann; Dong Hong Wang; Elaine M Smith; Thomas H Haugen; Lubomir P Turek

doi:10.1128/JVI.02093-10

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Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

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Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

Michael J Lace, James R Anson, Jens P Klussmann, Dong Hong Wang, Elaine M Smith, Thomas H Haugen and Lubomir P Turek

Journal of virology, Vol.85(4), pp.1645-1654

02/2011

DOI: 10.1128/JVI.02093-10

PMCID: PMC3028875

PMID: 21123375

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Abstract

Many human papillomavirus (HPV)-positive high-grade lesions and cancers of the uterine cervix harbor integrated HPV genomes expressing the E6 and E7 oncogenes from chimeric virus-cell mRNAs, but less is known about HPV integration in head and neck cancer (HNC). Here we compared viral DNA status and E6-E7 mRNA sequences in HPV-16-positive HNC tumors to those in independent human keratinocyte cell clones derived from primary tonsillar or foreskin epithelia immortalized with HPV-16 genomes. Three of nine HNC tumors and epithelial clones containing unintegrated HPV-16 genomes expressed mRNAs spliced from HPV-16 SD880 to SA3358 and terminating at the viral early gene p(A) signal. In contrast, most integrated HPV genomes in six HNCs and a set of 31 keratinocyte clones expressed HPV-16 major early promoter (MEP)-initiated mRNAs spliced from viral SD880 directly to diverse cellular sequences, with a minority spliced to SA3358 followed by a cellular DNA junction. Sequence analysis of chimeric virus-cell mRNAs from HNC tumors and keratinocyte clones identified viral integration sites in a variety of chromosomes, with some located in or near growth control genes, including the c- myc protooncogene and the gene encoding FAP-1 phosphatase. Taken together, these findings support the hypothesis that HPV integration in cancers is a stochastic process resulting in clonal selection of aggressively expanding cells with altered gene expression of integrated HPV genomes and potential perturbations of cellular genes at or near viral integration sites. Furthermore, our results demonstrate that this selection also takes place and can be studied in primary human keratinocytes in culture.

Transformation and Oncogenesis

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Title: Subtitle: Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers
Creators: Michael J Lace - Veterans Affairs Medical Center
James R Anson - Veterans Affairs Medical Center
Jens P Klussmann - Veterans Affairs Medical Center
Dong Hong Wang - Veterans Affairs Medical Center
Elaine M Smith - Veterans Affairs Medical Center
Thomas H Haugen - Veterans Affairs Medical Center
Lubomir P Turek - Veterans Affairs Medical Center
Resource Type: Journal article
Publication Details: Journal of virology, Vol.85(4), pp.1645-1654
DOI: 10.1128/JVI.02093-10
PMID: 21123375
PMCID: PMC3028875
NLM abbreviation: J Virol
ISSN: 0022-538X
eISSN: 1098-5514
Publisher: American Society for Microbiology (ASM)
Language: English
Date published: 02/2011
Academic Unit: Epidemiology; Pathology; Otolaryngology
Record Identifier: 9984047877602771

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