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Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics

Currently, approximately 30%–55% of the patients with non–small cell lung cancer (NSCLC) develop recurrence due to minimal residual disease (MRD) after receiving surgical resection of the tumor. This study aims to develop an ultrasensitive and affordable fragmentomic assay for MRD detection in patie...

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Autores principales: Wang, Siwei, Xia, Zhijun, You, Jing, Gu, Xiaolan, Meng, Fanchen, Chen, Peng, Tang, Wanxiangfu, Bao, Hua, Zhang, Jingyuan, Wu, Xue, Shao, Yang, Wang, Jie, Zuo, Xianglin, Xu, Lin, Yin, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10228550/
https://www.ncbi.nlm.nih.gov/pubmed/37377889
http://dx.doi.org/10.1158/2767-9764.CRC-22-0363
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author Wang, Siwei
Xia, Zhijun
You, Jing
Gu, Xiaolan
Meng, Fanchen
Chen, Peng
Tang, Wanxiangfu
Bao, Hua
Zhang, Jingyuan
Wu, Xue
Shao, Yang
Wang, Jie
Zuo, Xianglin
Xu, Lin
Yin, Rong
author_facet Wang, Siwei
Xia, Zhijun
You, Jing
Gu, Xiaolan
Meng, Fanchen
Chen, Peng
Tang, Wanxiangfu
Bao, Hua
Zhang, Jingyuan
Wu, Xue
Shao, Yang
Wang, Jie
Zuo, Xianglin
Xu, Lin
Yin, Rong
author_sort Wang, Siwei
collection PubMed
description Currently, approximately 30%–55% of the patients with non–small cell lung cancer (NSCLC) develop recurrence due to minimal residual disease (MRD) after receiving surgical resection of the tumor. This study aims to develop an ultrasensitive and affordable fragmentomic assay for MRD detection in patients with NSCLC. A total of 87 patients with NSCLC, who received curative surgical resections (23 patients relapsed during follow-up), enrolled in this study. A total of 163 plasma samples, collected at 7 days and 6 months postsurgical, were used for both whole-genome sequencing (WGS) and targeted sequencing. WGS-based cell-free DNA (cfDNA) fragment profile was used to fit regularized Cox regression models, and leave-one-out cross-validation was further used to evaluate models’ performance. The models showed excellent performances in detecting patients with a high risk of recurrence. At 7 days postsurgical, the high-risk patients detected by our model showed an increased risk of 4.6 times, while the risk increased to 8.3 times at 6 months postsurgical. These fragmentomics determined higher risk compared with the targeted sequencing–based circulating mutations both at 7 days and 6 months postsurgical. The overall sensitivity for detecting patients with recurrence reached 78.3% while using both fragmentomics and mutation results from 7 days and 6 months postsurgical, which increased from the 43.5% sensitivity by using only the circulating mutations. The fragmentomics showed great sensitivity in predicting patient recurrence compared with the traditional circulating mutation, especially after the surgery for early-stage NSCLC, therefore exhibiting great potential to guide adjuvant therapeutics. SIGNIFICANCE: The circulating tumor DNA mutation-based approach shows limited performance in MRD detection, especially for landmark MRD detection at an early-stage cancer after surgery. Here, we describe a cfDNA fragmentomics–based method in MRD detection of resectable NSCLC using WGS, and the cfDNA fragmentomics showed a great sensitivity in predicting prognosis.
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spelling pubmed-102285502023-05-31 Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics Wang, Siwei Xia, Zhijun You, Jing Gu, Xiaolan Meng, Fanchen Chen, Peng Tang, Wanxiangfu Bao, Hua Zhang, Jingyuan Wu, Xue Shao, Yang Wang, Jie Zuo, Xianglin Xu, Lin Yin, Rong Cancer Res Commun Research Article Currently, approximately 30%–55% of the patients with non–small cell lung cancer (NSCLC) develop recurrence due to minimal residual disease (MRD) after receiving surgical resection of the tumor. This study aims to develop an ultrasensitive and affordable fragmentomic assay for MRD detection in patients with NSCLC. A total of 87 patients with NSCLC, who received curative surgical resections (23 patients relapsed during follow-up), enrolled in this study. A total of 163 plasma samples, collected at 7 days and 6 months postsurgical, were used for both whole-genome sequencing (WGS) and targeted sequencing. WGS-based cell-free DNA (cfDNA) fragment profile was used to fit regularized Cox regression models, and leave-one-out cross-validation was further used to evaluate models’ performance. The models showed excellent performances in detecting patients with a high risk of recurrence. At 7 days postsurgical, the high-risk patients detected by our model showed an increased risk of 4.6 times, while the risk increased to 8.3 times at 6 months postsurgical. These fragmentomics determined higher risk compared with the targeted sequencing–based circulating mutations both at 7 days and 6 months postsurgical. The overall sensitivity for detecting patients with recurrence reached 78.3% while using both fragmentomics and mutation results from 7 days and 6 months postsurgical, which increased from the 43.5% sensitivity by using only the circulating mutations. The fragmentomics showed great sensitivity in predicting patient recurrence compared with the traditional circulating mutation, especially after the surgery for early-stage NSCLC, therefore exhibiting great potential to guide adjuvant therapeutics. SIGNIFICANCE: The circulating tumor DNA mutation-based approach shows limited performance in MRD detection, especially for landmark MRD detection at an early-stage cancer after surgery. Here, we describe a cfDNA fragmentomics–based method in MRD detection of resectable NSCLC using WGS, and the cfDNA fragmentomics showed a great sensitivity in predicting prognosis. American Association for Cancer Research 2023-05-30 /pmc/articles/PMC10228550/ /pubmed/37377889 http://dx.doi.org/10.1158/2767-9764.CRC-22-0363 Text en © 2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
Wang, Siwei
Xia, Zhijun
You, Jing
Gu, Xiaolan
Meng, Fanchen
Chen, Peng
Tang, Wanxiangfu
Bao, Hua
Zhang, Jingyuan
Wu, Xue
Shao, Yang
Wang, Jie
Zuo, Xianglin
Xu, Lin
Yin, Rong
Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
title Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
title_full Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
title_fullStr Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
title_full_unstemmed Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
title_short Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
title_sort enhanced detection of landmark minimal residual disease in lung cancer using cell-free dna fragmentomics
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10228550/
https://www.ncbi.nlm.nih.gov/pubmed/37377889
http://dx.doi.org/10.1158/2767-9764.CRC-22-0363
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