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; M Steinberg; S Bass; X Wang; P Liu; M Mehrad; T Tucker; J S Lewis; R L Ferris; L Mirabello

doi:10.1016/j.annonc.2022.03.005

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

Ann Oncol. 2022 Jun;33(6):638-648. doi: 10.1016/j.annonc.2022.03.005. Epub 2022 Mar 16.

Authors

K A Lang Kuhs¹, D L Faden², L Chen³, D K Smith⁴, M Pinheiro⁵, C B Wood⁶, S Davis⁷, M Yeager⁸, J F Boland⁸, M Cullen⁸, M Steinberg⁸, S Bass⁸, X Wang⁹, P Liu¹⁰, M Mehrad¹¹, T Tucker¹², J S Lewis¹³, R L Ferris¹⁴, L Mirabello⁵

Affiliations

¹ Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, USA; Department of Medicine, Vanderbilt University Medical Cancer, Nashville, USA. Electronic address: krystle.kuhs@uky.edu.
² Department of Otolaryngology, Massachusetts Eye and Ear, Massachusetts General Hospital, Harvard Medical School, Boston, USA; Broad Institute of MIT and Harvard, Cambridge, USA.
³ Division of Cancer Biostatistics, Department of Internal Medicine and Biostatistics and Bioinformatics Shared Resource Facility, Markey Cancer Center, University of Kentucky, Lexington, USA.
⁴ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, USA.
⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, USA.
⁶ Department of Otolaryngology - Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, USA; Department of Otolaryngology - Head and Neck Surgery, University of Tennessee Health Science Center, Memphis, USA.
⁷ Department of Otolaryngology - Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, USA.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, USA; Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, USA.
⁹ Department of Pharmacology and Regenerative Medicine, The University of Illinois at Chicago, Chicago, USA.
¹⁰ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, USA.
¹¹ Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, USA.
¹² Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, USA.
¹³ Department of Otolaryngology - Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, USA.
¹⁴ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, USA; Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA.

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 HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival.

Patients and methods: 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.

Results: 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 (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 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).

Conclusions: HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.

Keywords: HPV16; HPV16 sublineages; HPV16 variants; OPC; oropharyngeal cancer; viral genome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Alphapapillomavirus*
Genetic Variation / genetics
Human papillomavirus 16 / genetics
Humans
Oropharyngeal Neoplasms* / pathology
Papillomaviridae
Papillomavirus Infections*
Prognosis

Abstract

Publication types

MeSH terms

Grants and funding