Abstract
BackgroundNext-generation sequencing (NGS) is an efficient and sensitive method to detect mutations from ctDNA. Many features and clinical conditions could significantly affect the concordance between ctDNA and corresponding tumor tissues. Our goal was to systematically investigate the critical factors contributing to different concordance between ctDNA and corresponding tumor tissues.MethodsWe recruited two groups of IIIB or IV lung cancer patients: The standard group to evaluate the accuracy of our method and the concordance between ctDNA and tumor tissues, and the study group with various clinical conditions. We applied our unique identification (UID) indexed capturing-based sequencing (UC-Seq) to ctDNA samples, and confirm the results by Droplet digital PCR (ddPCR).ResultsConsidering mutations detected from NGS of tumor tissues as golden standard, UC-Seq achieved overall 93.6% sensitivity for SNVs and Indels, and 0.8 Pearson correlation between tumor TMB and bTMB. Efficacious treatments, long sampling date (more than 2 weeks) between tumor tissues and ctDNA and low concentrations of cfDNA (less than 9 ng/ml) could significantly decrease the concordance between ctDNA and tumor tissues. About 84% mutations showed shorter mutant fragment length than that of wild-type fragments, and the AFs of mutations could be significantly enriched in small-size ctDNA.ConclusionsIn late-stage lung cancer patients, ctDNA generally has high concordance with tumor tissues. However it could be significantly affected by three clinical conditions which could dynamically change the content of ctDNA. Moreover, the detection limit could be further extended by enriching small-size ctDNA in the preparation of samples.
Highlights
Next-generation sequencing (NGS) is an efficient and sensitive method to detect mutations from Circulating tumor Deoxyribonucleic acid (DNA) (ctDNA)
We explored whether the blood Tumor mutational burden (TMB) from a small panel in Circulating tumor DNA (ctDNA) could properly reveal TMB of the corresponding tumor tissues
Efficacious treatments and long sampling date between tumor tissues and ctDNA could significantly decrease the concordance between ctDNA and corresponding tumor tissues, revealing that ctDNA could dynamically monitor the status of tumors
Summary
Next-generation sequencing (NGS) is an efficient and sensitive method to detect mutations from ctDNA. Though patients with early-stage lung cancer have high overall survival after surgery or stereotactic body radiation therapy, whose 5-year survival can be over 50%, advanced lung cancer patients might not get sufficient benefits from similar treatments [4]. It is estimated that about 69% of advanced NSCLC patients possess at least one potential actionable drug target, which enabled targeted therapies [4]. Based on personal tumor profiles of DNA aberrations, the concept of precision medicine arises to individually strategize treatments in advanced cancers, which has been widely recognized. PCR-based techniques, which could detect single DNA aberration per reaction at extremely high sensitivity, including Amplification-refractory mutation system (ARMS), droplet digital PCR (ddPCR) and BEAMing; 2. Sequencing-based techniques, which could detect multiple aberrations simultaneously, including whole genome sequencing (WGS), amplicon sequencing and target capture sequencing
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