ImportanceThe oral microbiota may be involved in development of head and neck squamous cell cancer (HNSCC), yet current evidence is largely limited to bacterial 16S amplicon sequencing or small retrospective case-control studies.ObjectiveTo test whether oral bacterial and fungal microbiomes are associated with subsequent risk of HNSCC development.Design, Setting, and ParticipantsProspective nested case-control study among participants providing oral samples in 3 epidemiological cohorts, the American Cancer Society Cancer Prevention Study II Nutrition Cohort, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and the Southern Community Cohort Study. Two hundred thirty-six patients who prospectively developed HNSCC were identified during a mean (SD) of 5.1 (3.6) years of follow-up. Control participants who remained HNSCC free were selected by 2:1 frequency matching on cohort, age, sex, race and ethnicity, and time since oral sample collection. Data analysis was conducted in 2023.ExposuresCharacterization of the oral bacterial microbiome using whole-genome shotgun sequencing and the oral fungal microbiome using internal transcribed spacer sequencing. Association of bacterial and fungal taxa with HNSCC was assessed by analysis of compositions of microbiomes with bias correction. Association with red and orange oral pathogen complexes was tested by logistic regression. A microbial risk score for HNSCC risk was calculated from risk-associated microbiota.Main Outcomes and MeasuresThe primary outcome was HNSCC incidence.ResultsThe study included 236 HNSCC case participants with a mean (SD) age of 60.9 (9.5) years and 24.6% women during a mean of 5.1 (3.6) years of follow-up, and 485 matched control participants. Overall microbiome diversity at baseline was not related to subsequent HNSCC risk; however 13 oral bacterial species were found to be differentially associated with development of HNSCC. The species included the newly identified Prevotella salivae, Streptococcus sanguinis, and Leptotrichia species, as well as several species belonging to beta and gamma Proteobacteria. The red/orange periodontal pathogen complex was moderately associated with HNSCC risk (odds ratio, 1.06 per 1 SD; 95% CI, 1.00-1.12). A 1-SD increase in microbial risk score (created based on 22 bacteria) was associated with a 50% increase in HNSCC risk (multivariate odds ratio, 1.50; 95% CI, 1.21-1.85). No fungal taxa associated with HNSCC risk were identified.Conclusions and RelevanceThis case-control study yielded compelling evidence that oral bacteria are a risk factor for HNSCC development. The identified bacteria and bacterial complexes hold promise, along with other risk factors, to identify high-risk individuals for personalized prevention of HNSCC.

中文翻译：

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口腔微生物组和头颈部鳞状细胞癌的后续风险


重要性口腔微生物群可能参与头颈部鳞状细胞癌 （HNSCC） 的发生，但目前的证据主要限于细菌 16S 扩增子测序或小型回顾性病例对照研究。目的检测口腔细菌和真菌微生物组是否与随后发生 HNSCC 的风险相关。设计、环境和参与者在 3 个流行病学队列中提供口腔样本的参与者中进行前瞻性嵌套病例对照研究，美国癌症协会癌症预防研究 II 营养队列，前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验，以及南方社区队列研究。在平均 5.1 （3.6） 年的随访中确定了 236 例前瞻性发展为 HNSCC 的患者。保持无 HNSCC 的对照参与者是通过 2：1 频率匹配选择队列、年龄、性别、种族和民族以及自口腔样本采集以来的时间。数据分析于 2023 年进行。通过分析微生物组的组成并进行偏倚校正来评估细菌和真菌类群与 HNSCC 的关联。通过 logistic 回归检验与红色和橙色口腔病原体复合物的相关性。根据风险相关微生物群计算 HNSCC 风险的微生物风险评分。主要结局和测量主要结局是 HNSCC 发生率。结果该研究包括 236 名平均 （SD） 年龄为 60.9 （9.5） 岁的 HNSCC 病例参与者和 24.6% 的女性，平均随访时间为 5.1 （3.6） 年，以及 485 名匹配的对照参与者。 基线时的总体微生物组多样性与随后的 HNSCC 风险无关;然而，发现 13 种口腔细菌与 HNSCC 的发生存在差异相关性。这些物种包括新发现的普雷沃氏菌唾液、血链球菌和钩端三胞菌属，以及属于 β 和 γ 变形菌门的几个物种。红色/橙色牙周病原体复合物与 HNSCC 风险中度相关 （比值比，1.06/1 SD;95% CI，1.00-1.12）。微生物风险评分 （基于 22 种细菌创建） 增加 1-SD 与 HNSCC 风险增加 50% 相关 （多变量比值比，1.50;95% CI，1.21-1.85）。未发现与 HNSCC 风险相关的真菌分类群。结论和相关性这项病例对照研究产生了令人信服的证据，证明口腔细菌是 HNSCC 发展的危险因素。已识别的细菌和细菌复合物与其他风险因素一起有望识别高危个体以进行 HNSCC 的个性化预防。