Downstream effects of HPV integration on survival/metastasis in oropharyngeal cancer

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ABSTRACT The incidence of human papillomavirus associated (HPV(+)) oropharyngeal squamous cell carcinoma (OPSCC) is rising in the US, to the point that it is now estimated to be more prevalent than cervical cancer. There are significant disparities in OPSCC, especially with respect to recurrence and survival, which is worse in African-American OPSCC patients compared to non-Hispanic White (NHW) OPSCC patients. Due to low HPV vaccine use rates and the decades long latency period between HPV infection and cancer diagnosis, HPV(+) OPSCC remains a major health concern. The 5 year survival rate for HPV(+) OPSCC patients is 80%, significantly lower than the estimated 90% for invasive breast cancer, and the most likely reason for death is distant metastasis. Limited data in African-Americans indicate 1.6-times worse survival compared to NHW OPSCC, with few HPV-specific studies in this racial group. Furthermore, due to the life-long detrimental treatment effects on quality of life for survivors, it is of great interest to identify a subset of patients who would benefit from de-escalated treatment. Our long term goal for the parent grant is to differentiate between HPV(+) patients who have a good prognosis and are most likely to benefit from de-escalated therapy and those who require the standard, or a more aggressive regimen. Our group first characterized the two main subtypes of HPV(+) OPSCC, identifying HPV integration into the host genome as the driving factor in determining tumor subtype. We furthermore showed that HPV integration status is associated with overall survival. In this proposal we will extend our parent grant plan to a cohort of African-American OPSCC patients from the Louisiana Tumor Registry to study three downstream effects of HPV integration identified by our group and others: an increase in the splicing of HPV oncogene E6 to E6*, a decrease in the tumor immune response, and a change in cell differentiation status. Each of these effects plays a role in determining metastasis and survival, however the mechanism of their effect and their relative contributions remain unclear. In aim 1, we will disentangle the above three effects of HPV integration on overall and disease-specific survival using 150 African-American OSPCC tumors from the Louisiana Tumor Registry, and we will compare these tumors to our NHW tumors from Michigan. In aim 2, we will examine the effects of the shift to expressing mainly the shorter E6* isoform instead of full length E6 in these tumors. This was observed by us and others to increase oxidative phosphorylation and potentially tumor mutational burden. These studies are a first critical step to understanding the molecular consequences of HPV(+) OPSCC in African-Americans to identify avenues to improve prognosis in this understudied group.