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

作　　者：赵龙[1] 杨长江 叶颖江[1] 申占龙[1] ZHAO Long;YANG Changjiang;YE Yingjiang;SHEN Zhanlong(Laboratory of Surgical Oncology,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research,Peking University People's Hospital,Beijing 100044,China)

机构地区：[1]北京大学人民医院,北京大学人民医院外科肿瘤研究室,北京市结直肠癌诊疗研究重点实验室,北京100044

出　　处：《肿瘤学杂志》2024年第6期439-448,共10页Journal of Chinese Oncology

基　　金：国家重点研发计划(2023YFA1800204);国家自然科学基金(81972240,82272841)。

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c BioPortal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。[Objective]To investigate the mutations of DNA polymerase e(POLE)and DNA poly-meraseδ1(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 mi-crosatellite instability(MSI)of wild-type and mutant-type POLE/POLD1 of CRC patients were de-tected 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 sur-vival(DFS)(P<0.001),and disease-specific survival(DSS)(P=0.0178).The CRC patients with mu-tated type of POLE/POLD1 exhibited a significantly higher MSI percentage and up-regulated ex-pression 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 rela-tive 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.

关 键 词：POLE突变 POLD1突变 结直肠肿瘤 生物信息学 免疫治疗 

分 类 号：R735.35[医药卫生—肿瘤] R735.37[医药卫生—临床医学]