Abstract 4893: Multi-modality sequencing of multiple HPV mediated oropharyngeal squamous cell carcinomas from single patients reveals synchrony in viral genomes yet discordant mutational profiles and signatures

Abstract

Abstract Human Papilloma Virus (HPV) mediated oropharyngeal squamous cell carcinoma (HPVmOPSCC) is increasing in prevalence in the United States, as are cases of patients with multiple, spatially distinct, HPVmOPSCCs (mHPVmOPSCC). Patients with mHPVmOPSCCs present a unique opportunity to study the biology of HPV mediated tumorigenesis in the oropharynx, which currently is poorly understood. We performed whole exome sequencing and RNA-Seq on 16 paired HPVmOPSCCs (eight patients) and whole genome sequencing of the viral genome using a HPV16 NGS assay described previously. Viral sequencing revealed considerable diversity between patients, across multiple viral sublineages. However, all tumor pairs from a given patient contained the same viral genome, with at most 2 clonal SNPs distinguishing the viruses within a pair. In contrast, tumor DNA sequencing revealed striking dissimilarity between tumors from a given patient. Seven of eight tumor pairs shared no overlapping somatic mutations with one pair sharing only six variants out of 277 (2%). Mutational signature analysis demonstrated a dominant APOBEC signature in six tumors. Tumor pairs showed striking discordance of mutational signatures. In 3/8 pairs, one tumor exhibited a nearly 100% pure APOBEC+ mutational profile, while the other was totally devoid of APOBEC-signature mutations. Here, we have demonstrated that spatially independent tumors, originating within the same individual, in the same tissue type, are caused by the same virus. Interesting, despite this shared etiology, the pair of tumors within a patient develop with vastly different mutational profiles and have different mutational processes driving tumorigenesis. This suggests that despite infection by a single oncogenic virus, HPVmOPSCCs may develop via multiple, disparate pathways. Of particular interest is the tumor pairs' clear discordance in APOBEC mutational burden, which challenges existing hypotheses on the role of APOBEC mutagenesis in this disease. Citation Format: Daniel L. Faden, Adam Langenbucher, Krystle Kuhs, James S. Lewis, Michael S. Lawrence, Lisa Mirabello, Robert L. Ferris. Multi-modality sequencing of multiple HPV mediated oropharyngeal squamous cell carcinomas from single patients reveals synchrony in viral genomes yet discordant mutational profiles and signatures [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4893.