Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases

doi:10.1186/s13041-021-00886-4

	Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases
	Xu, Yanjun; Huang, Zhiyu; Yu, Xiaoqing; Chen, Kaiyan; Fan, Yun
刊名	MOLECULAR BRAIN
	2021-12-24
卷号	14
关键词	Brain metastases Predictive biomarker DNA methylation Somatic mutation Advanced non-small cell lung cancer (advanced NSCLC)
DOI	10.1186/s13041-021-00886-4
通讯作者	Fan, Yun(fanyun@zjcc.org.cn)
英文摘要	Background Brain metastasis is a common and lethal complication of non-small cell lung cancer (NSCLC). It is mostly diagnosed only after symptoms develop, at which point very few treatment options are available. Therefore, patients who have an increased risk of developing brain metastasis need to be identified early. Our study aimed to identify genomic and epigenomic biomarkers for predicting brain metastasis risk in NSCLC patients. Methods Paired primary lung tumor tissues and either brain metastatic tissues or cerebrospinal fluid (CSF) samples were collected from 29 patients with treatment-naive advanced NSCLC with central nervous system (CNS) metastases. A control group comprising 31 patients with advanced NSCLC who died without ever developing CNS metastasis was also included. Somatic mutations and DNA methylation levels were examined through capture-based targeted sequencing with a 520-gene panel and targeted bisulfite sequencing with an 80,672 CpG panel. Results Compared to primary lung lesions, brain metastatic tissues harbored numerous unique copy number variations. The tumor mutational burden was comparable between brain metastatic tissue (P = 0.168)/CSF (P = 0.445) and their paired primary lung tumor samples. Kelch-like ECH-associated protein (KEAP1) mutations were detected in primary lung tumor and brain metastatic tissue samples of patients with brain metastasis. KEAP1 mutation rate was significantly higher in patients with brain metastasis than those without (P = 0.031). DNA methylation analysis revealed 15 differentially methylated blocks between primary lung tumors of patients with and without CNS metastasis. A brain metastasis risk prediction model based on these 15 differentially methylated blocks had an area under the curve of 0.94, with 87.1% sensitivity and 82.8% specificity. Conclusions Our analyses revealed 15 differentially methylated blocks in primary lung tumor tissues, which can differentiate patients with and without CNS metastasis. These differentially methylated blocks may serve as predictive biomarkers for the risk of developing CNS metastasis in NSCLC. Additional larger studies are needed to validate the predictive value of these markers.
资助项目	National Natural Science Foundation of China[81972718] ; Zhejiang Provincial Natural Science Foundation[LY19H160007] ; Science and Technology Program for Health and Medicine in Zhejiang Province, China[2021KY541]
WOS关键词	CIRCULATING TUMOR DNA ; DIAGNOSIS ; MUTATIONS ; PROGNOSIS ; EVOLUTION ; SURVIVAL
WOS研究方向	Neurosciences & Neurology
语种	英语
出版者	BMC
WOS记录号	WOS:000734037500001
资助机构	National Natural Science Foundation of China ; Zhejiang Provincial Natural Science Foundation ; Science and Technology Program for Health and Medicine in Zhejiang Province, China
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/126926]
专题	中国科学院合肥物质科学研究院
通讯作者	Fan, Yun
作者单位	Chinese Acad Sci, Dept Med Thorac Oncol, Inst Basic Med & Canc IBMC, Canc Hosp,Univ Chinese Acad Sci,Zhejiang Canc Hos, 1 East Banshan Rd, Hangzhou 310022, Peoples R China
推荐引用方式 GB/T 7714	Xu, Yanjun,Huang, Zhiyu,Yu, Xiaoqing,et al. Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases[J]. MOLECULAR BRAIN,2021,14.
APA	Xu, Yanjun,Huang, Zhiyu,Yu, Xiaoqing,Chen, Kaiyan,&Fan, Yun.(2021).Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases.MOLECULAR BRAIN,14.
MLA	Xu, Yanjun,et al."Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases".MOLECULAR BRAIN 14(2021).