The Effect of Tobacco Exposure on Genomic Heterogeneity in HPV-Positive Oropharyngeal Squamous Cell Carcinoma

Dr. Jose Zevallos

While HPV(-) OPSCC often portends a grim prognosis, HPV(+) OPSCC outcomes are comparably favorable, with approximately 15% of HPV(+) OPSCC patients experiencing treatment failure. For most patients who respond to treatment, the morbidity associated with surgery, radiation therapy, and/or platinum-based chemotherapy is substantial and lifelong. The extent to which this treatment morbidity is justified by favorable oncologic outcomes is not clear, and treatment de-intensification for this patient group is a major focus of recent and ongoing clinical trials in HPV(+) OPSCC. The unique challenges in the future of HPV(+) OPSCC treatment are reducing iatrogenic morbidity through treatment de-intensification in low-risk individuals while also improving outcomes in the minority of patients who do not respond to the current standard of care therapies. Importantly, both tasks rely on accurately predicting high or low-risk disease. The work funded by the MGI pilot grant has led to two findings that could have a potential impact in improving the identification of high-risk individuals with HPV(+) OPSCC.  Dr. Zevallos’s team has validated the findings of another group which demonstrated that FGFR3 activating mutations portend a worse prognosis in HPV(+) OPSCC. They also found that an established NanoString gene expression profile, which has been previously validated as a predictor to response to immunotherapy in clinical trials, also has potential prognostic benefit. These findings may be translatable to the clinic through the use of personal tumor sequencing or NanoString assays and have implications on the future of personalized medicine and HPV(+) OPSCC treatment stratification. Preliminary results of this work were presented at the 2020 AACR virtual conference by Dr. Paul Zolkind.

Dr. Zevallos sought to elucidate molecular features underlying tobacco users with HPV(+) OPSCC, a group that has an attenuated prognosis relative to non-users of tobacco. Whole exome sequencing (WES) revealed previously described as well as novel somatic mutations. One mutation of interest is B2M, a component of the MHC-I complex. Mutations in MHC-I complex genes were associated with higher mutational and neoantigen burden, suggesting immune escape as an important part of the pathogenesis in a subset of patients. Exome sequencing also revealed that FGFR3 activating mutations are common in HPV(+) OPSCC and that FGFR3 activation through somatic mutations or copy number gains is significantly associated with treatment failure. A previously validated T cell-depleted gene expression profile (GEP) using NanoString transcripts revealed that an immune depleted tumor microenvironment (TME) was significantly associated with lower disease-free survival and overall survival as well as current tobacco use. Our results elucidate the role of the antitumor immune response in HPV(+) OPSCC as both a selective pressure for somatic mutations and as a prognostic feature that may contribute to the attenuated prognosis of tobacco users.

Since the team has completed whole genome HPV sequencing. They are collaborating with Dr. Jin Zhang Ph.D. within the Department of Radiation Oncology, at Washington University in St. Louis,  to analyze these data.  The results, initiated from a different cohort, suggest the potential importance of HPV structural subtypes as a prognostic feature in HPV(+) OPSCC.  Dr. Zevallos plans to complete an analysis of these data and prepare a second manuscript focused more on structural features of HPV, such as integration status, several viral copies sequenced, and how this relates to the tumor microenvironment and copy number.

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