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

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

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 r...

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Autores principales: 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
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/74f63e07641a43ec9278ce5ec5a27f64
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spelling oai:doaj.org-article:74f63e07641a43ec9278ce5ec5a27f642021-12-02T19:06:29ZLiquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations10.1038/s41598-021-95985-62045-2322https://doaj.org/article/74f63e07641a43ec9278ce5ec5a27f642021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95985-6https://doaj.org/toc/2045-2322Abstract 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.Hoai-Nghia NguyenNgoc-Phuong Thi CaoThien-Chi Van NguyenKhang Nguyen Duy LeDat Thanh NguyenQuynh-Tho Thi NguyenThai-Hoa Thi NguyenChu Van NguyenHa Thu LeMai-Lan Thi NguyenTrieu Vu NguyenVu Uyen TranBac An LuongLinh Gia Hoang LeQuoc Chuong HoHong-Anh Thi PhamBinh Thanh VoLuan Thanh NguyenAnh-Thu Huynh DangSinh Duy NguyenDuc Minh DoThanh-Thuy Thi DoAnh Vu HoangKiet Truong DinhMinh-Duy PhanHoa GiangLe Son TranNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
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
Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations
description 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.
format article
author 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
author_facet 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
author_sort Hoai-Nghia Nguyen
title Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations
title_short Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations
title_full Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations
title_fullStr Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations
title_full_unstemmed Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations
title_sort liquid biopsy uncovers distinct patterns of dna methylation and copy number changes in nsclc patients with different egfr-tki resistant mutations
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/74f63e07641a43ec9278ce5ec5a27f64
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