“磨玻璃影”特征的早期肺腺癌中MPP成分的突变特征分析及ZNF469基因的探索  

Mutational Signatures Analysis of Micropapillary Components and Exploration of ZNF469 Gene in Early-stage Lung Adenocarcinoma with Ground-glass Opacities

作　　者：许有涛[1] 孙钦泓 王思炜 朱鸿宇 董国璋 孟凡尘 夏志军 游静 孔祥茹 吴金涛 陈鹏[1] 袁方慰 余新宇 季金芾 李知桐 朱鹏程 孙宇翔 刘桐言[1] 尹荣[1] 许林[1] Youtao XU;Qinhong SUN;Siwei WANG;Hongyu ZHU;Guozhang DONG;Fanchen MENG;Zhijun XIA;Jing YOU;Xiangru KONG;Jintao WU;Peng CHEN;Fangwei YUAN;Xinyu YU;Jinfu JI;Zhitong Li;Pengcheng Zhu;Yuxiang Sun;Tongyan LIU;Rong YIN;Lin XU(Department of Thoracic Surgery,the Affiliated Cancer Hospital of Nanjing Medical University,Jiangsu Cancer Hospital,Jiangsu Institute of Cancer Research,Jiangsu Key Laboratory of Molecular and Translation Cancer Research,Nanjing 210009,China)

机构地区：[1]南京医科大学附属肿瘤医院,江苏省肿瘤医院胸外科,江苏省肿瘤防治研究所,江苏省恶性肿瘤分子生物学及转化医学重点实验室,南京210009

出　　处：《中国肺癌杂志》2023年第12期889-900,共12页Chinese Journal of Lung Cancer

基　　金：国家自然科学基金项目(No.82203202)资助。

摘　　要：背景与目的目前,肺癌依然是我国发病率和死亡率最高的恶性肿瘤。而在早期肺腺癌(lung adenocarcinoma,LUAD)中,微乳头(micropapillary,MPP)成分尤其常见,且通常表现出高侵袭性,其与早期转移、淋巴浸润的风险以及患者的5年生存率显著相关。本研究旨在探究以磨玻璃影(ground-glass opacities,GGOs)为特征的早期LUAD中MPP成分和非MPP成分的异同,寻找MPP成分所特有的突变特征,并分析锌指蛋白家族的ZNF469基因与早期LUAD预后以及免疫浸润的关系。方法收集31例LUAD恶性肺结节,采用显微解剖法将其分为成对的MPP和非MPP成分。对早期恶性肺结节组分进行全外显子组测序(whole-exome sequencing,WES),利用maftools、非负矩阵分解(Nonnegative Matrix Factorization,NMF)法、Sigminer等方法进行突变特征分析,以揭示侵袭性LUAD中MPP组分相比于其他肿瘤组织所特有的基因组突变特征。利用癌症基因组图谱(The Cancer Genome Atlas,TCGA)的LUAD数据库中ZNF469的表达情况,探讨其与肺癌预后的关系;利用GeneMANIA数据库以及基因本体(Gene Ontology,GO)、京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析探索LUAD中与ZNF469相关基因的互作网络及信号通路;利用TIMER和TISIDB数据库分析ZNF469表达与LUAD中免疫细胞浸润水平的相关性。结果MPP成分具有较多的基因组变异,相比于非MPP成分的肿瘤组织,癌症体细胞突变目录(Catalogue of Somatic Mutations in Cancer,COSMIC)的13号突变特征(胞苷脱氨酶家族,APOBEC)是MPP成分所特有的,这提示其参与了MPP成分对LUAD早期侵袭过程的促进作用;并且APOBEC特征高的MPP样本具有更高的肿瘤突变负荷(tumor mutational burden,TMB),提示这些患者更能从免疫治疗中获益。LUAD中突变ZNF469的表达高于正常组织,与LUAD患者的不良预后有关。基因互作网络分析以及GO和KEGG富集分析发现,COL6A1、COL1A1、COL1A2、TGFB2、MMP2、Background and objective In China,lung cancer remains the cancer with the highest incidence and mortality rate.Among early-stage lung adenocarcinomas(LUAD),the micropapillary(MPP)component is prevalent and typically exhibits high aggressiveness,significantly correlating with early metastasis,lymphatic infiltration,and reduced five-year survival rates.Therefore,the study is to explore the similarities and differences between MPP and non-micropapillary(non-MPP)components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD,identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene,a member of the zinc-finger protein family,and the prognosis of early-stage LUAD,as well as its correlation with immune infiltration.Methods A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection.Whole-exome sequencing(WES)was performed on the components of early-stage malignant pulmonary nodules.Mutational signatures analysis was conducted using R packages such as maftools,Nonnegative Matrix Factorization(NMF),and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues.Furthermore,we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas(TCGA)database to investigate its potential association with the prognosis.We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.Lastly,we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases.Results MPP components exhibited a higher number of genomic variations,particularly the 13th COSMIC(Catalogue of Somatic Mutations in Cancer)mutational signature characterized by the activity of the cytidine de

关 键 词：肺肿瘤 磨玻璃影 微乳头成分 突变特征分析 ZNF469基因 

分 类 号：R734.2[医药卫生—肿瘤]