Genome‐Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR‐TKI Resistance and Heterogeneous Responses. (December 2021)

• Record Type: Journal Article
• Authors: Su, Sheng‐Fang; Liu, Chia‐Hsin; Cheng, Chiou‐Ling; Ho, Chao‐Chi; Yang, Tsung‐Ying; Chen, Kun‐Chieh; Hsu, Kuo‐Hsuan; Tseng, Jeng‐Sen; Chen, Huei‐Wen; Chang, Gee‐Chen; Yu, Sung‐Liang; Li, Ker‐Chau
• Is Part Of: JCO precision oncology. Volume 5(2021)
• Publication Date: 2021-12
• Subjects: Precision Medicine; Neoplasms; Pharmacogenetics; Molecular Targeted Therapy; Personalized medicine; Oncology; Pharmacogenomics; Periodical; Periodicals; 616.994
• DOI: 10.1200/PO.20.00151
• Languages: English
• ISSNs: 2473-4284

Abstract

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 [OR], 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.