High-Risk Human Papillomavirus in Head and Neck Squamous Cell Carcinoma.

Human Papillomavirus;Head and Neck Squamous Cell Carcinoma;Oropharyngeal Cancer;HPV Integration;High-risk HPV;HPV-induced Cancer;Medicine (General);Health Sciences;Cancer Biology

Walline, Heather MarieBeer, David G. ;

University of Michigan

关键词: Human Papillomavirus;    Head and Neck Squamous Cell Carcinoma;    Oropharyngeal Cancer;    HPV Integration;    High-risk HPV;    HPV-induced Cancer;    Medicine (General);    Health Sciences;    Cancer Biology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/102428/hwalline_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

High-risk human papillomavirus (hrHPV)-driven carcinogenesis is the predominant etiologic factor in oropharyngeal squamous cell carcinoma (OPSCC). Most HPV-positive OPSCCs respond well to therapy, prompting interest in reducing treatment intensities, but approximately 20% fail to respond to therapy and recur for unknown reasons.The prognostic value of HPV in OPSCC warrants a universal standard for hrHPV assessment, and evaluation of factors that may differentiate responsive from non-responsive tumors is needed to determine the optimal treatment for patients.We compared hrHPV detection by PCR-MassArray, p16INK4a immunohistochemistry, and HPV in situ hybridization in oropharynx, nasopharynx, and oral cavity tumors to determine the optimal assessment of hrHPV.HPV copy number, viral oncogene expression, integration sites, and integration transcripts were examined in seven HPV-positive HNSCC cell lines from patients who progressed, plus five responsive and five recurrent OPSCC tumors.Using combined PCR-MA with L1 consensus PCR and sequencing for resolving discordant results, we found PCR-MA to have the greatest sensitivity and specificity of the methods evaluated, making it optimal for HPV detection in combination with p16 for correlative viral activity.Of 338 tumors, 183/212 (86%) of oropharynx, 9/18 (50%) of nasopharynx and 28/108 (26%) of oral cavity tumors were positive for hrHPV. All of the HPV-positive cell lines and tumors evaluated expressed HPV E6 and E7 oncogenes and exhibited alternate splicing, indicating active viral oncogenesis.Each of the HPV-positive cell lines, which came from non-responsive outlier tumors, and the five recurrent tumors exhibited HPV integration into cancer–associated cellular genes.Each of the responsive tumors demonstrated viral integration into non-genic chromosome regions, with only one integration into a cancer-related gene.Integration transcript analysis revealed HPV-cellular fusion transcripts, intact cellular transcripts, and several genomic rearrangements, indicating genomic instability in the cell.We propose that viral integration is an early carcinogenic event, associated with disruption of the E1/E2 region and alternate E6*I transcription, leading to increased viral oncogene expression as the carcinogenic driver in responsive tumors.Further, we hypothesize that HPV integration into cellular genes may result in secondary alterations in cellular gene expression or dysfunction, resulting in a more aggressive malignant phenotype resistant to current therapy.