| 赵 龙,杨长江,叶颖江,等.POLE/POLD1突变对结直肠癌预后及免疫治疗影响的生物信息学分析[J].肿瘤学杂志,2024,30(6):439-448. |
| POLE/POLD1突变对结直肠癌预后及免疫治疗影响的生物信息学分析 |
| POLE/POLD1 Mutation in Colorectal Cancer and Its Relation with Immunotherapy and Prognosis of Patients: Analysis Based on Bioinformatics |
| 投稿时间：2023-08-10 |
| DOI：10.11735/j.issn.1671-170X.2024.06.B001 |
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| 中文关键词: POLE突变 POLD1突变 结直肠肿瘤 生物信息学 免疫治疗 |
| 英文关键词:POLE mutation POLD1 mutation colorectal neoplasms bioinformatics immunity |
| 基金项目:国家重点研发计划（2023YFA1800204）；国家自然科学基金（81972240，82272841） |
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| 中文摘要: |
| 摘 要： ［目的］ 利用生物信息学方法对结直肠癌（colorectal cancer，CRC）中的DNA聚合酶ε（POLE）和DNA聚合酶δ1（POLD1）的突变情况进行分析，并探索两者对CRC预后及免疫治疗的影响。［方法］ 基于TCGA数据库的数据集，利用cBioPortal工具对所有癌症中的POLE/POLD1的改变及其预后进行分析，利用MSIsensor、MANTIS两种评分系统对POLE/POLD1野生型和突变型的CRC患者微卫星不稳定性进行评价，并利用TIMER数据库分析CRC的免疫细胞浸润以及免疫检查点表达与POLE/POLD1突变之间相关性。［结果］ 在CRC中POLE/POLD1基因的改变频率为6%，且均以错义突变为主。在泛癌中POLE的突变后患者无进展生存期(P<0.001)、无病生存期(P<0.001)及疾病特异性生存期(P=0.017 8)均显著延长。POLE/POLD1突变型CRC患者的微卫星不稳定性占比相比较于野生型患者显著提高(P<0.001)，且免疫检查点相关基因CD274、HAVCR2、PDCD1、CTLA4、LAG3、TIGIT和PDCD1LG2的表达均显著上升。CRC中POLE和POLD1基因表达均与肿瘤突变负荷显著相关。此外，CRC中POLE/POLD1突变还与CD8+ T细胞、中性粒细胞、树突状细胞等免疫细胞的浸润相关。 ［结论］ POLE/POLD1基因的改变在CRC中较为常见，在泛癌中POLD1突变与患者预后相关。POLE/POLD1基因突变后可能造成微卫星不稳定性增高、免疫检查点的表达上调和免疫细胞浸润程度增加，其可能成为免疫治疗的新靶点。 |
| 英文摘要: |
| Abstracts：［Objective］ To investigate the mutations of DNA polymerase ε (POLE) and DNA polymerase δ1(POLD1) in colorectal cancer(CRC) and their relation with immunotherapy and prognosis of patients. ［Methods］ Using The Cancer Genome Atlas(TCGA) database， the mutations of POLE/POLD1 gene and prognosis of pan-cancer patients were analyzed with the cBioPortal tool. The microsatellite instability(MSI) of wild-type and mutant-type POLE/POLD1 of CRC patients were detected by the two scoring systems of MSIsensor and MANTIS. The correlation of POLE/POLD1 mutation with immune cell infiltration and immune checkpoint expression in CRC was analyzed by the TIMER database. ［Results］ The mutation frequency of the POLE/POLD1 gene in CRC was 6%， predominantly consisting of missense mutations. In pan-cancer， patients with mutations in POLE showed significantly prolonged progression-free survival(PFS)(P<0.001)， disease-free survival(DFS)(P<0.001)， and disease-specific survival(DSS)(P=0.017 8). The CRC patients with mutated type of POLE/POLD1 exhibited a significantly higher MSI percentage and up-regulated expression of immune checkpoint-related genes CD274， HAVCR2， PDCD1， CTLA4， LAG3， TIGIT and PDCD1LG2， compared to CRC patients with the wild-type(P<0.001). The expression of POLE and POLD1 genes in CRC was significantly correlated with tumor mutation burden. Furthermore， the mutation in POLE/POLD1 in CRC was associated with the infiltration of immune cells such as CD8+ T cells， neutrophils and dendritic cells. ［Conclusion］ Mutations on POLE/POLD1 are relative common in CRC， and mutations of POLD1 are related to the prognosis of patients in pan-cancer. Mutations on the POLE/POLD1 gene may cause increased MSI， up-regulated expression of immune checkpoint genes， and increased immune cell infiltration， indicating that POLE/POLD1 gene might be used as a novel target for immunotherapy. |
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