Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Response

doi:10.1200/PO.20.00151

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/24102

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/24102

Title:	Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Response
Authors:	Su, SF;Liu, CH;Cheng, CL;Ho, CC;Yang, TY;Chen, KC;Hsu, KH;Tseng, JS;Chen, HW;Chang, GC;Yu, SL;Li, KC
Date:	2021
Issue Date:	2022-08-05T09:47:51Z (UTC)
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Abstract:	PURPOSE Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) show efficacy in treating patients with lung adenocarcinoma with EGFR-activating mutations. However, a significant subset of targeted patients fail to respond. Unlike acquired resistance (AR), intrinsic resistance (IR) remains poorly understood. We investigated whether epigenomic factors contribute to patient-to-patient heterogeneity in the EGFR-TKI response and aimed to characterize the IR subpopulation that obtains no benefit from EGFR-TKIs. PATIENTS AND METHODS We conducted genome-wide DNA methylation profiling of 79 tumors sampled from patients with advanced lung adenocarcinoma before they received EGFR-TKI treatment and analyzed the patient responses. Pyrosequencing was performed in a validation cohort of 163 patients with EGFR-activating mutations. RESULTS A DNA methylation landscape of 216 CpG sites with differential methylation was established to elucidate the association of DNA methylation with the characteristics and EGFR-TKI response status of the patients. Functional analysis of 37 transcription-repressive sites identified the enrichment of transcription factors, notably homeobox (HOX) genes. DNA methylation of HOXB9 (cg13643585) in the enhancer region yielded 88% sensitivity for predicting drug response (odds ratio FOR], 6.64; 95% CI, 1.98 to 25.23; P= .0009). Pyrosequencing validated that HOXB9 gained methylation in patients with a poor EGFR-TKI response (OR, 3.06; 95% CI, 1.13 to 8.19; P = .019). CONCLUSION Our data suggest that homeobox DNA methylation could be a novel tumor cellular state that can aid the precise categorization of tumor heterogeneity in the study of IR to EGFR-TKIs. We identified, for the first time, an epigenomic factor that can potentially complement DNA mutation status in discriminating patients with lung adenocarcinoma who are less likely to benefit from EGFR-TKI treatment, thereby leading to improved patient management in precision medicine. (C) 2021 by American Society of Clinical Oncology
URI:	http://dx.doi.org/10.1200/PO.20.00151 https://www.webofscience.com/wos/woscc/full-record/WOS:000636555100002 https://ir.csmu.edu.tw:8080/handle/310902500/24102
Relation:	JCO PRECISION ONCOLOGY ,2021,v5 , P418-431
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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