Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma

Zhiyong Deng,Xuefeng Xia,Zhi Tang,Zhengwen He,Rongrong Zhou,Yanfang Guan,Zhe Zhong,Haofeng Cheng,Liang Cui,Xin Yi,Jianwu Gong,Pansong Li,Nianjun Ren,Lei Wang

doi:10.1038/s41419-021-04223-4

Abstract

Lung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.

Highlights

Lung adenocarcinoma (LUAD) is the most common histologic subtype in non-small cell lung cancers (NSCLC) and accounts for more than 38.5% of all lung cancers [1]
Tumor mutation burden and copy number variation instability of the Cerebrospinal fluid (CSF) and primary lung tumors A 1021 panel sequencing was performed on CSF, ESLT, LSLT-noBM, and LSLT-Brain metastasis (BM) groups with the average depth of 1583, 1230, 1271, and 1254×, respectively
In the current study, we analyzed genomic profile difference of Chinese LUAD patients between CSF samples and other primary lung tissues from different disease stages, and proved the unique molecular characteristics of CSF samples from multiple aspects, such as single nucleotide variation (SNV), copy number variation (CNV), signature, clonality and pathway, and revealed CSF cell-free DNA (cfDNA) was an important medium to expound the molecular features of BM LUAD patients, which provided potential prognostic markers and therapeutic targets for LUAD with BMs

Summary

Introduction

Lung adenocarcinoma (LUAD) is the most common histologic subtype in non-small cell lung cancers (NSCLC) and accounts for more than 38.5% of all lung cancers [1]. BMs in lung cancer patients (20–56%) are the most commonly arising compared with other tumor types [3]. The risk of BMs will be increased with increasing tumor grade [5], which has a negative impact on the life quality of patients with LUAD. Cerebrospinal fluid (CSF), containing cell-free DNA (cfDNA), had been considered as a vital liquid biopsy medium for lung cancer, which provides a less-invasive and routinely accessible method to dynamically acquire genomic information of BM patients in lung cancer [6]. Previous studies had revealed CSF circulating tumor DNA (ctDNA) was more representative of brain tumor genomic alterations than plasma, and could detect brain tumor private mutations and monitor brain tumor progression [7,8,9]

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Conclusion