Antibodies to HPV16, particularly the E6 oncoprotein, are strongly associated with HPV16-driven cervical cancer (CaCx), however they are a late event in tumor development (low prevalence in women with CIN3), and about half of women with HPV16-driven invasive CaCx do not seroconvert. In contrast, HPV16 E6 antibodies show >95% sensitivity and specificity for detection of HPV16-driven oropharyngeal cancer (HPV-OPC) in cross-sectional studies, and were shown to precede OPC tumor diagnosis by more than 10 years in prospective cohort studies.
Antibodies to HPV16 L1, E1, E2, E4, E6, and E7 proteins in serum or plasma samples from two case series collected in Europe and the US, and two prospective studies, the European Prospective Investigation into Cancer and Nutrition (EPIC), and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), were analyzed by multiplex serology. Tumor HPV status was determined by HPV in-situ hybridization (ISH), HPV DNA detection, HPV RNA patterns (E6*I, E1^E4 and E1C), and p16 immunohistochemistry (IHC).
Antibodies to HPV16 E6 were shown to be almost exclusively present in cases with HPV-driven OPC, yielding both sensitivity and specificity exceeding 95%. At the same time, odds ratios for OPC prediction on average >6 years prior to diagnosis were >150. Serial annual samples (median 5 per individual) taken up to 13 years prior to OPC diagnosis showed strong and stable antibody levels.
HPV 16 serological markers, especially antibodies to E6, are strongly associated with OPC more than 10 years prior to clinical tumor diagnosis. To date, the trigger for seroconversion (e.g., infection of the tonsils or base of tongue, malignant transformation of tonsillar crypt epithelium, yet to be described early OPC lesions) is not understood, and the clinical implications of early HPV-OPC detection are under debate.