HPV Associated Cancers
Approximately 150 million Americans have been infected with human papillomavirus (HPV), and another 6.2 million people become newly infected each year. In cervical cancer, progression from infection of high-risk HPV subtypes to carcinoma is infrequent and can occur over decades, suggesting that HPV infection is necessary but not sufficient for carcinogenesis. HPV has recently been associated with up to 75% of oropharyngeal cancer, which has profound implications both for the risk of oral transmission, as well as HPV vaccination strategies. The natural history of oral HPV infection is unknown as there are no standard assays for monitoring either pathologic changes (i.e. Pap smear), viral load or immunity and no known precancerous lesions. A biomarker panel for early detection of at-risk populations and for predicting recurrence would have a clear impact on the management of HPV-associated cancers.
We have developed novel bead-based arrays for high-throughput serologic screening of antibodies to the HPV16 proteome. This approach uses mammalian in vitro expression of cDNAs encoding protein antigens, capture of antigens using anti-tag antibodies (Abs), and then binding and detection of Abs from patient sera. Because this approach is based on cDNA and expression of structural epitopes, it allows for greater flexibility and economy in antigen selection and epitope mapping. We have identified antibodies to E1, E2, E4, E6, and E7 antigens in patients with oropharyngeal cancer, but not healthy controls. We have also detected antibodies primarily to E6 and E7 in patients with invasive cervical cancer but not CIN II/III, demonstrating these are biomarkers of cancer, not HPV infection. The heterogeneity of immune responses in these patient populations suggests that there are fundamental biologic differences in host/viral biology within patients with OPC.
We are currently determining which antigens within high-risk HPVs generate measurable B cell immunity (antibodies) in patients with HPV-associated cancers. We are generating custom protein microarrays expressing the genomes of 13 high-risk and 2 low-risk HPV types for serum screening. We predict that these antibodies may be useful as biomarkers for early detection and recurrence of HPV-associated cancers. In addition, we are examining the protein structure/function relationships of HPV-derived early-gene proteins, to develop novel HPV-targeted therapeutics.
Anderson KS, Wong J, D’Souza G, Riemer AB, Lorch J, Haddad R, Pai S, Longtine J, Bryan J, McClean M, LaBaer J, Kelsey KT, and Posner M. Serum Antibodies to the HPV16 Proteome As Biomarkers For Head and Neck Cancer. Brit. J. Cancer 2011 June;104(12): 1896-905. PMID: 21654689. PMCID: PMC3111202. doi:10.1038/bjc.2011.171
D’Souza G, Gross N, Pai SI, Haddad R, Anderson KS, Rajan S, Gerber J, Gillison ML, Posner M. Oral HPV infection in HPV-positive oropharyngeal cancer cases and their partners, Journal of Clinical Oncology, 2014