Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, USA; Department of Medicine, Vanderbilt University Medical Cancer, Nashville, USA.
Department of Otolaryngology, Massachusetts Eye and Ear, Massachusetts General Hospital, Harvard Medical School, Boston, USA; Broad Institute of MIT and Harvard, Cambridge, USA.
Ann Oncol. 2022 Jun;33(6):638-648. doi: 10.1016/j.annonc.2022.03.005. Epub 2022 Mar 16.
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 (HR): 3.75, 95% CI 1.77-7.95; P = 0.0099]; L2 gene positions 4410 (HR: 5.32, 95% CI 1.91-14.81; P = 0.0120), 4539 (HR: 6.54, 95% CI 2.03-21.08; P = 0.0117); 5050 (HR: 6.53, 95% CI 2.34-18.24; P = 0.0030), and 5254 (HR: 7.76, 95% CI 2.41-24.98; P = 0.0030); and L1 gene positions 5962 (HR: 4.40, 95% CI 1.88-10.31; P = 0.0110) and 6025 (HR: 5.71, 95% CI 2.43-13.41; P = 0.0008) and position 7173 within the upstream regulatory region (HR: 9.90, 95% CI 3.05-32.12; P = 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.
人乳头瘤病毒（HPV）驱动的口咽癌（HPV-OPC）采用降级治疗方案的一个主要障碍是预后不良的预测因素很少。我们进行了首次大规模全基因组测序（WGS）研究，以描述 HPV16 基因组的遗传变异，并评估其与 HPV-OPC 患者生存的关系。
两个美国大型医疗中心（1980-2017 年）的 460 例 OPC 肿瘤标本进行了 HPV16 全基因组测序。确定了 HPV16 基因组中特定位置的单核苷酸多态性（SNP）。Cox 比例风险模型估计了 HPV16 SNP 对总生存率的风险比（HR）和 95%置信区间（CI）。Harrell C 指数和时间依赖性阳性预测值（PPV）曲线及其曲线下面积用于评估 HPV16 SNP 对总生存率的预测准确性。
通过 HPV16 基因组测序的足够深度和覆盖范围，质量控制过滤后有 384 例 OPC 肿瘤标本（83.48%）通过质量控制。确定了 284 个具有≥1%的次要等位基因频率的 HPV16 SNP。在假发现率校正后，有 8 个 HPV16 SNP 与较差的生存显著相关（个体患病率：1.0%-5.5%；联合患病率：15.10%）；E1 基因位置 1053 [总生存率的 HR（HR）：3.75，95%CI 1.77-7.95；P = 0.0099]；L2 基因位置 4410（HR：5.32，95%CI 1.91-14.81；P = 0.0120），4539（HR：6.54，95%CI 2.03-21.08；P = 0.0117）；5050（HR：6.53，95%CI 2.34-18.24；P = 0.0030）和 5254（HR：7.76，95%CI 2.41-24.98；P = 0.0030）；L1 基因位置 5962（HR：4.40，95%CI 1.88-10.31；P = 0.0110）和 6025（HR：5.71，95%CI 2.43-13.41；P = 0.0008）以及上游调控区的位置 7173（HR：9.90，95%CI 3.05-32.12；P = 0.0007）。有≥1 个高危 HPV16 SNP 的患者的中位生存时间为 3.96 年，而无高危 SNP 的患者为 18.67 年；对数秩检验 P < 0.001。HPV16 SNP 显著提高了传统因素（年龄、吸烟、分期、治疗）以上的总体生存率预测准确性；C 指数增加 0.069（95%CI 0.019-0.119，P < 0.001）；预测 5 年生存率的 PPV 曲线下面积增加 0.068（95%CI 0.015-0.111，P = 0.008）。
HPV16 遗传变异与 HPV-OPC 预后相关，可提高预后准确性。
