Shing Jaimie Z, Giuliano Anna R, Brenner Nicole, Michels Birgitta, Hildesheim Allan, Srivastava Sudhir, Sirak Bradley A, Schussler John, Liu Danping, Wang Wendy, Waterboer Tim, Kreimer Aimée R
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20850, United States.
Center for Immunization and Infection Research in Cancer, Moffitt Cancer Center, Tampa, FL 33612, United States.
J Natl Cancer Inst. 2025 May 1;117(5):915-923. doi: 10.1093/jnci/djae326.
Human papillomavirus (HPV) type 16 E6 protein seropositivity accurately predicts oropharyngeal squamous cell carcinoma risk decades before diagnosis; but the biomarker's translational potential is unknown. To inform considerations for oropharyngeal squamous cell carcinoma screening, we described HPV-16 E6 seroprevalence, predictors, and kinetics among cancer-free men.
In a cohort study in Brazil, Mexico, and the United States, we calculated HPV-16 E6 seropositivity (median fluorescence intensity > 1000), measured by multiplex serology, in cancer-free men. We assessed HPV-16 E6 seropositivity predictors using logistic regression, adjusting for country, age, sexual orientation, and lifetime number of sexual partners. Among HPV-16 E6 seropositive men, we retrieved all available retrospective serum samples and described temporal HPV-16 E6 antibody patterns.
Of 3997 men, 14 had HPV-16 E6 antibodies detected (seroprevalence = 0.35%, 95% CI = 0.19% to 0.59%; median fluorescence intensity = 2407 [IQR = 1325-5986]). Older age was associated with increased odds of HPV-16 E6 seropositivity (50-84 years vs 18-29 years odds ratio = 16.61, 95% CI = 2.20 to 417.03). Serum from 11 of the 14 seropositive men retested positive; 6 men had median fluorescence intensity above 5000, of whom 2 had median fluorescence intensity greater than 10 000. Seven men had 3 or more years of follow-up; all were persistently seropositive for 3 years. One man was seropositive for 9 years but seroreverted at his exit visit. Oral HPV-16 DNA (prevalence = 1.13%) was associated with HPV-16 E6 seropositivity (odds ratio = 16.87, 95% CI = 3.35 to 69.55), but oral HPV-16 DNA positivity was not persistent over follow-up, even when HPV-16 E6 antibodies were persistently detected.
Although HPV-16 E6 seropositivity is rare, it is generally stable once detected; thus, HPV-16 E6 antibodies may be an informative biomarker of HPV-driven oropharyngeal squamous cell carcinoma. Few men seroreverted following HPV-16 E6 seropositivity but remained close to the seropositivity cutoff; thus, cancer risk among these men is less clear.
16型人乳头瘤病毒（HPV）E6蛋白血清学阳性可在诊断前数十年准确预测口咽鳞状细胞癌风险；但该生物标志物的转化潜力尚不清楚。为了为口咽鳞状细胞癌筛查的考量提供信息，我们描述了无癌男性中HPV-16 E6血清阳性率、预测因素及变化情况。
在巴西、墨西哥和美国进行的一项队列研究中，我们通过多重血清学检测计算了无癌男性中HPV-16 E6血清学阳性（中位荧光强度>1000）情况。我们使用逻辑回归评估HPV-16 E6血清学阳性的预测因素，并对国家、年龄、性取向和性伴侣终身数量进行了调整。在HPV-16 E6血清学阳性的男性中，我们检索了所有可用的回顾性血清样本，并描述了HPV-16 E6抗体的时间模式。
在3997名男性中，有14人检测到HPV-16 E6抗体（血清阳性率=0.35%，95%置信区间=0.19%至0.59%；中位荧光强度=2407[四分位间距=1325 - 5986]）。年龄较大与HPV-16 E6血清学阳性几率增加相关（50 - 84岁与18 - 29岁相比，优势比=16.61，95%置信区间=2.20至417.03）。14名血清学阳性男性中有11人的血清重新检测呈阳性；6名男性的中位荧光强度高于5000，其中2名男性的中位荧光强度大于10000。7名男性有3年或更长时间的随访；所有男性在3年内持续血清学阳性。1名男性血清学阳性9年，但在最后一次随访时血清学转阴。口腔HPV-16 DNA（患病率=1.13%）与HPV-16 E6血清学阳性相关（优势比=16.87，95%置信区间=3.35至69.55），但即使持续检测到HPV-16 E6抗体，口腔HPV-16 DNA阳性在随访期间也不持续。
虽然HPV-16 E6血清学阳性很少见，但一旦检测到通常是稳定的；因此，HPV-16 E6抗体可能是HPV驱动的口咽鳞状细胞癌的一个有参考价值的生物标志物。少数男性在HPV-16 E6血清学阳性后血清学转阴，但仍接近血清学阳性临界值；因此，这些男性的癌症风险尚不清楚。
