LBPO.PR01 · 预防研究 · Late-Breaking
口腔癌前病变-癌症谱系中的生态变迁与微生物组重组
Ecological shifts and microbiome reorganization across oral precancer-cancer spectrum
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：
口腔鳞状细胞癌（OCSCC）及其前驱病变——口腔潜在恶性疾病（OPMD），发生于复杂的黏膜微环境中，微生物组可能参与致癌过程。在这项横断面观察性研究中，我们旨在比较正常口腔黏膜、OPMD 和 OCSCC 的细菌群落，以确定特定的组成变迁或多样性模式是否与疾病进展相关。
方法：
81 例接受临床评估的 OPMD（n=55）或 OCSCC（n=26）患者，从病变部位及对侧临床正常黏膜采集了部位匹配的拭子标本。12 例无 OPMD 或任何恶性肿瘤的患者作为对照。由 16S rRNA 基因扩增子测序数据生成的扩增子序列变体（ASV）在属水平上进行分类归属。采用配对 Wilcoxon 检验在患者内部比较 α 多样性（丰富度、Shannon、逆 Simpson 指数），并采用非参数检验在各诊断组间进行比较。β 多样性（Bray-Curtis）通过主坐标分析（PCoA）结合 PERMANOVA 进行评估，以估计效应量（R²）和 p 值。绘制冲积图和维恩图以评估各组间的重叠以及组间与组内多样性。
结果：
横断面上，在所有指标中，对照组、异型增生病变和癌症病变之间的 α 多样性无显著差异。相比之下，全部各组的 PCoA 显示按疾病状态存在轻度但具有统计学意义的组成分离（PERMANOVA F=2.191，R²=0.052，p=0.001）；在癌症患者中，病变部位与对侧正常部位显示出一种趋势（F=1.159，R²=0.028，p=0.055）；在异型增生患者中，分离程度极小但名义上显著（F=0.647，R²=0.009，p=0.025）。总体而言，49% 的属在癌症病变、异型增生病变和对照组之间共享，而 20% 的属为异型增生病变特有，10% 的属为癌症病变特有。最后，异型增生病变和癌症病变的组内 Bray-Curtis 距离均高于对照组（FDR 校正后 p<0.001），与恶性转化过程中渐进性生态多样化相一致。
结论：
在这项跨越正常黏膜、OPMD 和 OCSCC 的、样本量相对较大且部位匹配的横断面队列中，口腔致癌过程以 β 多样性的变迁为特征。关键发现包括：异型增生病变相对于配对黏膜的均匀度显著升高，按疾病状态存在微小但显著的组成差异（R² ≈ 5%），以及异型增生病变和癌症病变内部特有 ASV 的增加。这些结果支持这样一种模型：口腔致癌过程与微生物组的细微生态重组相关，而非其粗大破坏，并突显了可供机制研究和生物标志物研究的候选细菌类群。
查看英文原文 English abstract
Introduction:
Oral cavity squamous cell carcinoma (OCSCC) and their precursor lesions, oral potentially malignant diseases (OPMD), arise within a complex mucosal microenvironment where the microbiome may contribute to carcinogenesis. In this cross-sectional observational study, we aimed to compare the bacterial communities of normal oral mucosa, OPMD, and OCSCC to determine whether specific compositional shifts or diversity patterns are associated with progressive disease.
Methods:
Eighty-one patients with OPMD (n=55) or OCSCC (n=26) undergoing clinical evaluation had site-matched swabs from lesions and contralateral clinically normal mucosa. Twelve patients without OPMD or any malignancy served as controls. Amplicon sequence variants (ASVs) generated from 16S rRNA gene amplicon sequencing data were taxonomically assigned to genus level. Alpha diversity (richness, Shannon, inverse Simpson) was compared within patients using paired Wilcoxon tests and across diagnostic groups using nonparametric tests. Beta diversity (Bray-Curtis) was assessed by principal coordinates analysis (PCoA) with PERMANOVA to estimate effect size (R²) and p values. Alluvial plots and Venn diagrams were generated to evaluate overlap between groups and inter and intra group diversity.
Results:
Cross-sectionally, alpha diversity did not differ significantly among controls, dysplasia lesions, and cancer lesions across all metrics. In contrast, PCoA of all groups showed modest but statistically significant compositional separation by disease status (PERMANOVA F=2.191, R²=0.052, p=0.001); within cancer patients, lesion versus contralateral normal sites showed a trend (F=1.159, R²=0.028, p=0.055), and within dysplasia patients, separation was minimal but nominally significant (F=0.647, R²=0.009, p=0.025). Overall, 49% of genera were shared among cancer lesions, dysplasia lesions, and controls, while 20% of genera were unique to dysplasia lesions and 10% were unique to cancer lesions. Lastly, both dysplasia and cancer lesions demonstrated higher intragroup Bay-Curtis distances compared with controls (FDR-adj. p<0.001), consistent with a progressive ecological diversification in malignant transformation.
Conclusion:
In this comparatively large, site-matched cross-sectional cohort spanning normal mucosa, OPMD, and OCSCC, oral carcinogenesis was characterized by shifts in beta diversity. Key findings include significantly increased evenness in dysplasia lesions relative to paired mucosa, small yet significant compositional differences by disease status (R² ≈ 5%), and an increase in unique ASVs within dyplasia and cancer lesions. These results support a model in which oral carcinogenesis is associated with subtle ecological reorganization rather than gross disruption of the microbiome and highlight candidate bacterial taxa for mechanistic and biomarker studies.
利益披露 Disclosure
A. Maniakas,
Rakuten Medical ).
Jazz Pharmaceuticals ).
Thryv Therapeutics Inc ).
NABORS Industries ).
Z. R. Neale, None..
J. Wargo, None..
J. N. Myers, None..
N. Ajami, None..
A. G. Sikora, None..
L. E. Colbert, None.