Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations

• Main Authors: Hoai-Nghia Nguyen, Ngoc-Phuong Thi Cao, Thien-Chi Van Nguyen, Khang Nguyen Duy Le, Dat Thanh Nguyen, Quynh-Tho Thi Nguyen, Thai-Hoa Thi Nguyen, Chu Van Nguyen, Ha Thu Le, Mai-Lan Thi Nguyen, Trieu Vu Nguyen, Vu Uyen Tran, Bac An Luong, Linh Gia Hoang Le, Quoc Chuong Ho, Hong-Anh Thi Pham, Binh Thanh Vo, Luan Thanh Nguyen, Anh-Thu Huynh Dang, Sinh Duy Nguyen, Duc Minh Do, Thanh-Thuy Thi Do, Anh Vu Hoang, Kiet Truong Dinh, Minh-Duy Phan, Hoa Giang, Le Son Tran
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-08-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-021-95985-6

Abstract Targeted therapy with tyrosine kinase inhibitors (TKI) provides survival benefits to a majority of patients with non-small cell lung cancer (NSCLC). However, resistance to TKI almost always develops after treatment. Although genetic and epigenetic alterations have each been shown to drive resistance to TKI in cell line models, clinical evidence for their contribution in the acquisition of resistance remains limited. Here, we employed liquid biopsy for simultaneous analysis of genetic and epigenetic changes in 122 Vietnamese NSCLC patients undergoing TKI therapy and displaying acquired resistance. We detected multiple profiles of resistance mutations in 51 patients (41.8%). Of those, genetic alterations in EGFR, particularly EGFR amplification (n = 6), showed pronounced genome instability and genome-wide hypomethylation. Interestingly, the level of hypomethylation was associated with the duration of response to TKI treatment. We also detected hypermethylation in regulatory regions of Homeobox genes which are known to be involved in tumor differentiation. In contrast, such changes were not observed in cases with MET (n = 4) and HER2 (n = 4) amplification. Thus, our study showed that liquid biopsy could provide important insights into the heterogeneity of TKI resistance mechanisms in NSCLC patients, providing essential information for prediction of resistance and selection of subsequent treatment.