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Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis
Journal article   Open access   Peer reviewed

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

K.A. Lang Kuhs, D.L. Faden, L. Chen, D.K. Smith, M. Pinheiro, C.B. Wood, S. Davis, M. Yeager, J.F. Boland, M. Cullen, …
Annals of oncology, Vol.33(6), pp.638-648
06/01/2022
DOI: 10.1016/j.annonc.2022.03.005
PMCID: PMC9350957
PMID: 35306154
url
https://doi.org/10.1016/j.annonc.2022.03.005View
Published (Version of record) Open Access

Abstract

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 HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival. A total of 460 OPC tumor specimens from two large United States medical centers (1980-2017) underwent HPV16 whole-genome sequencing. Site-specific variable positions [single nucleotide polymorphisms (SNPs)] across the HPV16 genome were identified. Cox proportional hazards model 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. A total of 384 OPC tumor specimens (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. Some 284 HPV16 SNPs with a minor allele frequency ≥1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate correction (individual prevalence: 1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 [HR for overall survival (HRos): 3.75, 95% CI 1.77-7.95; Pfdr = 0.0099]; L2 gene positions 4410 (HRos: 5.32, 95% CI 1.91-14.81; Pfdr = 0.0120), 4539 (HRos: 6.54, 95% CI 2.03-21.08; Pfdr = 0.0117); 5050 (HRos: 6.53, 95% CI 2.34-18.24; Pfdr = 0.0030), and 5254 (HRos: 7.76, 95% CI 2.41–24.98; Pfdr = 0.0030); and L1 gene positions 5962 (HRos: 4.40, 95% CI 1.88-10.31; Pfdr = 0.0110) and 6025 (HRos: 5.71, 95% CI 2.43-13.41; Pfdr = 0.0008) and position 7173 within the upstream regulatory region (HRos: 9.90, 95% CI 3.05-32.12; Pfdr = 0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared with 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). HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy. •Few prognostic markers of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) exist.•We conducted the first large HPV16 whole-genome sequencing study of 384 HPV16+OPCs•We found eight HPV16 SNPs to be strongly associated with HPV-OPC prognosis.•Median survival was 4 years for HPV-OPC patients with ≥1 high-risk HPV16 SNPs versus 19 years for patients without.•HPV16 SNPs improved predictive accuracy for HPV-OPC overall survival compared with age, stage, treatment and smoking alone.
 HPV16 HPV16 sublineages HPV16 variants OPC oropharyngeal cancer viral genome sequencing

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