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J Mol Diagn. 2017 Jan;19(1):169-181. doi: 10.1016/j.jmoldx.2016.09.008. Epub 2016 Nov 19.

Application of Single-Molecule Amplification and Resequencing Technology for Broad Surveillance of Plasma Mutations in Patients with Advanced Lung Adenocarcinoma.

Author information

1
Department of Pathology, Beijing Hospital, National Center of Gerontology, Beijing, China.
2
Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China.
3
Department of Medical Oncology, Cancer Institute and Hospital Chinese Academy of Medical Sciences, Beijing, China.
4
Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing, China.
5
Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
6
Department of Medical Oncology, Military General Hospital of Beijing PLA, Beijing, China.
7
Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China.
8
Department of Medical Oncology, Air Force General Hospital of Beijing PLA, Beijing, China.
9
Department of Respiratory Medicine, The First Affiliated Hospital of General Hospital of PLA, Beijing, China.
10
Research and Development Department, Berry Genomics Corp., Beijing, China.
11
Department of Medical Oncology, Cancer Institute and Hospital Chinese Academy of Medical Sciences, Beijing, China. Electronic address: syuankaipumc@126.com.
12
Department of Pathology, Beijing Hospital, National Center of Gerontology, Beijing, China. Electronic address: liudongge@sohu.com.

Abstract

Liquid biopsy to access the circulating tumor DNA is a promising surrogate for invasive tumor genotyping. We designed a multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART) to simultaneously detect and quantitate hot spot EGFR, KRAS, BRAF, ERBB2, and ALK plasma DNA variants in 103 patients with advanced lung adenocarcinoma. In validation studies using an analytical mutation standard, the sensitivity of the assay for EGFR mutation detection was at least 0.1% and specificity was 100%. The diagnostic detection sensitivity was one mutant molecule per 2 mL of plasma. The most frequently detected plasma mutations were EGFR variants L858R (21.4%), exon 19 deletions (19.4%), T790M (9.7%), and KRAS G12X variants (9.7%). Rarer were BRAF V600X (1.95%) and ERBB2 exon 20 (0.97%) variants. In single samples, four novel EGFR exon 19 deletions, one KIF5B-ALK, and two EML4-ALK variants were also detected. From comparisons of 103 matched plasma and tumor specimen genotypes, 75 (72.8%) were concordant, 9 (8.8%) were partially concordant, and 19 (18.4%) were discordant. Overall, the combined positive and negative concordance rate for detection of each oncogenic variant exceeded 90%. On the basis of these findings, we propose that cSMART displays the diagnostic hallmarks of a comprehensive plasma genotyping assay, with potential application for precisely monitoring changes in plasma mutation levels in response to targeted drug therapy.

PMID:
27870944
DOI:
10.1016/j.jmoldx.2016.09.008
[Indexed for MEDLINE]

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