In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 8543-8543
Abstract:
8543 Background: A better understanding of molecular mechanisms governing clonal tumor evolution under RCHT is of utmost importance for development of novel biomarker and targeted therapies. We report here the first attempt to decipher RCHT induced cellular and molecular perturbation in NSCLC on an integrative multiscale level. Methods: Patients with stage III disease received induction chemotherapy with cisplatin and paclitaxel followed by concurrent RCHT with 45 Gy (1.5 Gy twice daily) and cisplatin/vinorelbine according to the ESPATUE protocol. Tumor tissue was sampled from tumor enriched areas marked by pathologists at diagnosis (biopsies, n= 23) and post RCHT during surgical resection (n=22, ESPATUE-Arm B) corresponding to 16 paired samples (PS). Transcriptome analysis (n=45, 16PS), methylome analysis (n=35, 12PS), deep whole exome sequencing (WES) including copy number variation (CNV) analysis by low-pass whole genome sequencing (WGS, n=34, 13PS) were performed. A confirmatory targeted ultra-deep NGS for 41 genes was conducted (n=20PS). Results: Similarity plots of delta transcriptome data identified three distinct clusters of tumor evolution under RCHT. Cluster 1 was highly enriched for STS (5 out of 7 Pat.) compared to cluster 3 enriched for LTS (4 out of 6), p 〈 0.02. 146 transcripts were differentially expressed as the function of RCHT (FDR 〈 0.05). Among them, 61 genes were upregulated and enriched for ECM and tissue remodeling (COL6A3/4, Col14A1, LAMA2, PAI1, MMP2), p53 signaling (p21, GADD45B) and stress response (FOSB, EGR1) pathways, p 〈 0.01. 39 downregulated genes were enriched for genes attributed to cell cycle- and DDR signaling (FANCI, SLX1A) p 〈 0.05. 4221 CpG were differentially methylated (FDR 〈 0.05). Seven inversely regulated genes were found with SLIT3 and TBX5 being among upregulated and hypomethylated genes. WES analysis revealed patterns of tumor evolution with a range of clonal diversity. In 5/13 pairs the clonal composition remained unchanged after RCHT. Approximately 500 post RCHT exclusive mutations were found. Conclusions: Clonal, transcriptional and methylome dynamic of tumor evolution towards RCHT selection pressure is unrevealed in patients with locally advanced NSCLC. This multi-scale dynamic approach provides novel means for development of biomarker and therapeutic targets. Clinical trial information: ESPATUE.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2019.37.15_suppl.8543
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2019
detail.hit.zdb_id:
2005181-5
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