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Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma
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Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma
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Journal Article
Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma
2021
Overview
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 45/23
/ 45/29
/ 45/70
/ 45/77
/ Adenocarcinoma of Lung - cerebrospinal fluid
/ Adenocarcinoma of Lung - genetics
/ Adult
/ Aged
/ Biomedical and Life Sciences
/ Brain Neoplasms - cerebrospinal fluid
/ Cancer
/ DNA Copy Number Variations - genetics
/ Epidermal growth factor receptors
/ Female
/ Fibroblast growth factor receptor 4
/ Genetic Predisposition to Disease
/ Genomics
/ Genotype
/ Humans
/ Lung Neoplasms - cerebrospinal fluid
/ Male
/ Polymorphism, Single Nucleotide - genetics
