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Cell-Cycle and DNA-Damage Response Pathway Is Involved In Published OnlineFirst October 13, 2017; DOI: 10.1158/1078-0432.CCR-17-1582 Biology of Human Tumors Clinical Cancer Research Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non–Small Cell Lung Cancer Yun Fan1, Xuehua Zhu2, Yan Xu3, Xuesong Lu4, Yanjun Xu1, Mengzhao Wang3, Haiyan Xu4, Jingyan Ding2, Xin Ye2, Luo Fang5, Zhiyu Huang5, Lei Gong5, Hongyang Lu1, Weimin Mao1, and Min Hu2 Abstract Purpose: Leptomeningeal metastasis (LM) is a detrimental risk. Intriguingly, low overlapping of somatic protein-changing complication of non–small cell lung cancer (NSCLC) and asso- variants was observed between paired CSF and primary lesions, ciated with poor prognosis. However, the underlying mechanisms exhibiting tumor heterogeneity and genetic divergence. Moreover, of the metastasis process are still poorly understood. genes with CSF-recurrent genomic alterations were predominant- Experimental Design: We performed next-generation panel ly involved in cell-cycle regulation and DNA-damage response sequencing of primary tumor tissue, cerebrospinal fluid (CSF), (DDR), suggesting a role of the pathway in LM development. and matched normal controls from epidermal growth factor Conclusions: Our study has shed light on the genomic varia- receptor (EGFR) mutation-positive NSCLC patients with LM. tions of NSCLC-LM, demonstrated genetic heterogeneity and Results: The status of EGFR-activating mutations was highly divergence, uncovered involvement of cell-cycle and DDR path- concordant between primary tumor and CSF. PIK3CA aberrations way, and paved the way for potential therapeutic approaches to were high in these patients, implicating an association with LM this unmet medical need. Clin Cancer Res; 24(1); 209–16. Ó2017 AACR. Introduction LM is defined as the spread of malignant cells to the leptome- ninges and throughout the subarachnoid space, and dissemina- Approximately 10% to 15% of patients with non–small cell tion of tumors cells into the cerebrospinal fluid (CSF) compart- lung cancer (NSCLC) in Western countries and 40% to 55% in ment. About 9% to 10% of patients with NSCLC with EGFR- Asia harbor epidermal growth factor receptor (EGFR)-activating activating mutations will develop LM either at initial diagnosis or mutations such as L858R and exon 19 deletion (19Del). EGFR during TKI treatment (9, 10). LM is often associated with poor tyrosine kinase inhibitors (TKIs) have opened up an era of target prognosis and represents a terminal event of NSCLC. The median therapy in NSCLC and markedly extended progression-free sur- overall survival (OS) after LM diagnosis is 3.1 to 11 months, with vival (PFS) of patients with EGFR-activating mutations (1–6). 60% death due to LM or LM together with systemic lesions (9– However, there have been reports of cumulative incidence of 13). So far, there is no effective treatment, though preliminary central nervous system (CNS) metastases over time (7, 8). Diag- clinical activities of osimertinib and AZD3759 in patients with nosis and treatment of leptomeningeal metastases (LM), a form of NSCLC with LM have been reported (14, 15), and other CNS- CNS metastases, remain particularly challenging. penetrant TKIs such as tesevatinib are being developed. Moreover, the mechanisms underlying the metastasis process are not eluci- dated yet. Further research is warranted to understand the genetic 1Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China. 2IMED Asia, AstraZeneca, alternations driving the metastasis and to develop treatment Shanghai, China. 3Department of Respiratory Medicine, Peking Union Medical strategies that improve the survival of patients with NSCLC-LM. College Hospital, Chinese Academy of Medical Sciences, Beijing, China. Plasma circulating tumor DNA (ctDNA) has been shown to 4Research & Development Information, AstraZeneca, Shanghai, China. 5Zhejiang effectively reflect tumor-specific genomic alterations and has been Cancer Hospital, Hangzhou, Zhejiang, China. used to dynamically monitor tumor progression, response, and Note: Supplementary data for this article are available at Clinical Cancer relapse (16). However, due to blood–brain barrier (BBB), patients Research Online (http://clincancerres.aacrjournals.org/). with brain tumors do not present with or present with only low Y. Fan, X. Zhu, and Y. Xu contributed equally to this article. amounts of ctDNA in plasma (17). Recently, a few studies have Corresponding Authors: Min Hu, AstraZeneca, No. 199 Liangjing Road, Zhang- demonstrated that tumor mutations are detectable in the CSF of jiang Hi-tech Park, Pudong New Area, Shanghai 201203, China. Phone: 86-021- patients with various primary and metastatic brain tumors, and 61097820; Fax: 86-021-58387337; E-mail: [email protected]; and ctDNA in CSF recapitulates the genomic landscape of brain Yun Fan, Zhejiang Cancer Hospital, No. 1 Banshan East Road, Hangzhou, Zhejiang tumors better than plasma (18–20). Therefore, CSF may serve as 310022, China. Phone: 86-0571-88122396; Fax: 86-0571-88122396; E-mail: liquid biopsy to monitor brain tumor evolution. In this study, we [email protected] performed next-generation panel sequencing of matched primary doi: 10.1158/1078-0432.CCR-17-1582 tumor tissues, CSF samples and normal controls from 11 patients Ó2017 American Association for Cancer Research. with EGFR mutation-positive NSCLC to characterize genomic www.aacrjournals.org 209 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 13, 2017; DOI: 10.1158/1078-0432.CCR-17-1582 Fan et al. the LungPlasma panel (Burning Rock Biotech) covering 168 Translational Relevance cancer-associated genes (Supplementary Table S2). Enriched Approximately 10% of patients with non–small cell lung libraries were sequenced on NextSeq 500 sequencing system cancer (NSCLC) with epidermal growth factor receptor (Illumina) with 150-bp pair-end reads. For specimens from (EGFR)-activating mutations will develop leptomeningeal patients P4-11, targeted panel sequencing was performed using metastases (LMs) either at initial diagnosis or during treatment SeqCap EZ System (Roche Nimblegen) and captured by the of tyrosine kinase inhibitors (TKIs). LMs are often associated customized SeqCap EZ Choice Library (Roche Nimblegen) cov- with poor prognosis and represent a terminal event of NSCLC. ering 403 cancer-associated genes (Supplementary Table S3). So far, there is no effective treatment, and the mechanisms Enriched libraries were sequenced on HiSeq X10 sequencing underlying the metastasis process are not elucidated yet. Here, system (Illumina) with 150-bp pair-end reads. On-target average we performed next-generation panel sequencing of matched sequence depth (before deduplication): FFPE tissues >500Â primary tumors and cerebrospinal fluid (CSF) samples from except 300Â in P6T; blood >2,700Â; CSF >4,000Â except patients with EGFR mutation-positive NSCLC-LM, to charac- 1,880Â in P8C. terize genomic alterations during LM development and to understand signaling pathways implicated in this metastasis Bioinformatics data analysis process. Our results demonstrated the value of CSF as liquid BWA (21) was used for mapping the pair-end reads to human biopsy for monitoring LM evolution, the association of reference genome hg19, samblaster (22) for marking duplicate PIK3CA aberrations with LM risk, and the potential role of reads, and VarDict (23) for detection of single-nucleotide variants the cell-cycle and DNA-damage response pathway in LM (SNV) and insertions and deletions (indels). Information on development. microsatellite instability (MSI) was extracted from the output of VarDict. Analysis of structural rearrangements was carried out using ArrayStudio (OmicSoft). SNVs and indels were called with aberrations during LM development and to understand signaling the criteria of (i) variant allele frequency (VAF) 5% or 1% if pathways implicated in this metastasis process. associated with a COSMIC ID; and (ii) 3 supporting reads and 10 total reads after deduplication. Variant calls of hotspot Materials and Methods mutations and structural rearrangements were manually inspected and rescued. Patients and sample collection For tumor and CSF samples with patient-matched normal The 11 patients with NSCLC-LM were diagnosed at Zhejiang DNA, the somatic status was inferred by removing variants with Cancer Hospital and Peking Union Medical College Hospital VAF 10% in the normal control. For tumor and CSF samples during 2009 to 2015. EGFR mutation status of their primary without paired normal DNA, variants with VAF 10% in any of tumors was initially determined by amplification-refractory muta- the normal samples from other patients were filtered. tion system (ARMS) assay at the hospitals, as one of the inclusion Variants with 1% population prevalence in the Single Nucle- criteria. The study was approved by the hospital research ethics otide Polymorphism Database (dbSNP; https://www.ncbi.nlm. committees, and all patients had signed the informed consent nih.gov/snp/) were removed as common SNPs. form. Formalin-fixed paraffin-embedded (FFPE) tumor and nor- Protein-changing variants refer to SNVs and indels that fall into mal tissues and freshly frozen CSF and whole blood samples were functional categories of frameshift, nonsense, start/stop lost, collected for genomic profiling (Supplementary Table S1). All splice acceptor/donor, missense, and inframe insertion/deletion,
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