Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis

ABSTRACT Purpose A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV16 genome and to evaluate its association with HPV-OPC patient survival. Patients and Methods 460 OPCs from 2 large US medical centers (1980-2017) underwent HPV16 WGS. Site-specific variable positions (SNPs) across the HPV16 genome were identified. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival. Results 384 OPCs (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. 284 HPV16 SNPs with a minor allele frequency >1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate (FDR) correction (individual prevalence:1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 (HR for overall survival [HR os ]:3.75,95%CI:1.77-7.95; P fdr =0.0099); L2 gene positions 4410 (HR os 5.32,95%CI:1.91-14.81; P fdr =0.0120), 4539 (HR os 6.54,95%CI:2.03-21.08; P fdr =0.0117); 5050 (HR os 6.53,95%CI:2.34-18.24; P fdr =0.0030) and 5254 (HR os 7.76,95%CI:2.41-24.98; P fdr =0.0030); and L1 gene positions 5962 (HR os 4.40,95%CI:1.88-10.31; P fdr =0.0110) and 6025 (HR os 5.71,95%CI:2.43-13.41; P fdr =0.0008) and position 7173 within the upstream regulatory region (HR os 9.90,95%CI:3.05-32.12; P fdr =0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared to 18.67 years for patients without a high-risk SNP; log-rank test P <0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment): increase in C-index was 0.069 (95% CI: 0.019-0.119, P <0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95%CI: 0.015-0.111, P =0.008). Conclusions HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.