Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non-Small Cell Lung Cancer

Leptomeningeal metastasis (LM) is a detrimental complication of non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. We performed next-generation panel sequencing of primary tumor tissue, cere...

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Bibliographic Details
Published in:Clinical cancer research 2018-01, Vol.24 (1), p.209-216
Main Authors: Fan, Yun, Zhu, Xuehua, Xu, Yan, Lu, Xuesong, Xu, Yanjun, Wang, Mengzhao, Xu, Haiyan, Ding, Jingyan, Ye, Xin, Fang, Luo, Huang, Zhiyu, Gong, Lei, Lu, Hongyang, Mao, Weimin, Hu, Min
Format: Article
Language:English
Subjects:
Aberration
Cancer
Cerebrospinal fluid
Deoxyribonucleic acid
Divergence
DNA
DNA damage
Epidermal growth factor
Epidermal growth factor receptors
Experimental design
Gene expression
Genetic diversity
Heterogeneity
Lesions
Lung cancer
Meninges
Metastases
Metastasis
Mutation
Non-small cell lung carcinoma
Patients
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Summary:Leptomeningeal metastasis (LM) is a detrimental complication of non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor ( ) mutation-positive NSCLC patients with LM. The status of -activating mutations was highly concordant between primary tumor and CSF. aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development. Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. .
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-17-1582