Evidence for a causal association between human papillomavirus and a subset of head and neck cancers
Evidence for a causal association between human papillomavirus and a subset of head and neck cancers
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DOI：
10.1093/jnci/92.9.709
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发表时间：
2000-05-03
影响因子：
10.3
通讯作者：
Sidransky, D
中科院分区：
文献类型：
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作者：
Gillison, ML;Koch, WM;Sidransky, D
背景：高危人乳头瘤病毒（HPV）是肛门生殖道癌症的病原体，并已在头颈鳞状细胞癌（HNSCC）中检测到。我们回顾性研究了 HPV 在大量 HNSCC 患者中的病因学作用。方法：通过使用基于聚合酶链式反应 (PCR) 的检测、Southern 印迹杂交和原位杂交，检测 253 名新诊断或复发性 HNSCC 患者的肿瘤组织中是否存在 HPV 基因组。对病毒 E6 编码区进行测序，以确认肿瘤特异性病毒分离株的存在。对 166 个样本的 TP53 基因的外显子 5-9 进行了测序。通过比例风险回归分析确定患有和不患有 HPV 阳性肿瘤的患者死于 HNSCC 的风险。结果：253 例病例中有 62 例 (25%) 检测到 HPV（95% 置信区间 [CI] = 19%-30%），90% 的 HPV 阳性肿瘤中检测到高危致瘤型 HPV16。通过原位杂交，HPV16 被特异性定位在浸润前、浸润和淋巴结疾病的癌细胞核内。 Southern印迹杂交模式与病毒整合一致。肿瘤分级差（比值比 [OR] = 2.4；95% CI = 1.2-4.9）和口咽部位（OR = 6.2；95% CI = 3.1-12.1）独立增加 HPV 存在的可能性。与 HPV 阴性口咽癌相比，HPV 阳性口咽癌在中重度饮酒者 (OR = 0.17; 95% CI = 0.05-0.61) 和吸烟者 (OR = 0.16; 95% CI = 0.02-1.4) 中发生的可能性较小，具有特征性的基底细胞样形态 (OR = 18.7; 95% CI = 2.1-167），发生 TP53 突变的可能性较小（OR = 0.06；95% CI = 0.01-0.36），并且疾病特异性生存率有所改善（风险比 [HR] = 0.26；95% CI = 0.07-0.98）。调整淋巴结疾病（HR = 2.3；95% CI = 1.4-3.8）、酗酒（HR = 2.6；95% CI = 1.4-4.7）和年龄大于 60 岁（HR = 1.4；95% CI = 0.8-2.3）后，所有 HPV 阳性肿瘤患者的癌症死亡风险比对照组降低 59% HPV 阴性 HNSCC 患者（HR = 0.41；95% CI = 0.20-0.88）。结论：这些数据扩展了最近的分子和流行病学研究，强烈表明 HPV 阳性口咽癌包含一种独特的分子、临床和病理疾病实体，可能与 HPV 感染有因果关系，并且预后显着改善。
Background: High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. Methods: Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5-9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis. Results: HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%-30%), Highrisk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2- 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1-12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05-0.61) and smokers (OR = 0.16; 95% CI = 0.02-1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1-167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01-0.36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07-0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4-3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4-4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8-2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20-0.88). Conclusions: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.