基于在线数据库和真实世界样本探讨肺腺癌患者POLE/POLD1突变的临床意义

摘要 目的：POLE和POLD1突变导致DNA聚合酶校对功能丧失可能会影响基因组稳定性并导致突变增加和肿瘤形成。本文结合在线数据库和真实世界样本进一步分析肺腺癌（LUAD）患者POLE和/或 POLD1 突变的临床意义。方法：纳入2021年1月～2021年8月徐州医科大学附属医院肺癌术后组织标本115例，利用二代测序技术（NGS）检测基因突变；从癌症基因组图谱（TCGA）数据库收集肺腺癌数据集，通过Cbioportal在线数据库获得肿瘤突变分布图，通过Cibersort法计算获得样本的免疫相关细胞浸润情况。结果：真实世界样本中POLE/ POLD1突变的比例为7.83%（9/115）。TCGA数据显示POLE/POLD1突变的LUAD患者总生存期（OS）减少（P=0.0359）。然而，携带该突变的患者并发其他基因改变的频率明显增加，尤其是与TP53突变存在正相关；同时，POLE/POLD1突变与LUAD组织浸润性免疫杀伤细胞呈正相关，与免疫抑制细胞呈负相关，提示这部分患者对免疫检查点抑制剂（ICI）敏感。结论：LUAD患者POLE/POLD1突变预示较高的肿瘤突变负荷和免疫微环境改变，可作为ICI疗效预测的潜在生物标志物，值得临床关注。

Clinical Significance of POLE/POLD1 Mutation in Patients with Lung Adenocarcinoma Based on Online Database and Real-World Samples

ABSTRACT Objective: POLE and POLD1 mutations cause loss of DNA polymerase function, which may affect genome stability and lead to increased mutations and tumor formation. This article combines online databases and real world samples to further analyze the clinical significance of POLE and/or POLD1 mutations in lung adenocarcinoma (LUAD) patients. Methods: During Jan 2021 to Aug 2021,115 cases of postoperative LUAD tissue specimens were enrolled from the Affiliated Hospital of Xuzhou Medical University. Next-generation sequencing (NGS) was used to detect gene mutations. LUAD data sets were download from The Cancer Genome Atlas (TCGA) database, tumor mutation distribution maps were obtained through the Cbioportal online database, and the immune-related cell infiltration status of the samples were calculated through the Cibersort method. Results: The proportion of POLE/POLD1 mutations in real world samples was 7.83% (9/115). TCGA data shows that overall survival (OS) of LUAD patients with POLE/POLD1 mutations tend to have a worse prognosis (P=0.0359). However, patients with this mutation showed a higher mutation count, especially positively correlated with TP53 mutation; at the same time, POLE/POLD1 mutation was positively correlated with LUAD tissue infiltrating immune killer cells, and negatively correlated with immunosuppressive cells, suggesting these patients are sensitive to immune checkpoint inhibitor (ICI). Conclusion: POLE/POLD1 mutations in LUAD patients indicate higher tumor mutation burden and immune microenvironment changes, which can be used as potential biomarkers for the prediction of ICI efficacy and deserve more clinical attention.