التفاصيل البيبلوغرافية
| العنوان: |
Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses. |
| المؤلفون: |
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 |
| المصدر: |
JCO Precision Oncology; 5/10/2021, Vol. 5, p418-431, 14p |
| مصطلحات موضوعية: |
DNA methylation, EPIGENOMICS, EPIDERMAL growth factor receptors, METHYLATION, KINASE inhibitors |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
