한빛사논문
- 조회544
Kwang Seob Lee a,†, Jieun Seo a,†, Choong-Kun Lee b,c, Saeam Shin a, Zisun Choi d, Seungki Min d, Jun Hyuek Yang d, Woo Sun Kwon c, Woobin Yun e, Mi Ri Park a, Jong Rak Choi a,d, Hyun Cheol Chung b,c,f, Seung-Tae Lee a,d,* and Sun Young Rha b,c,f,*
aDepartment of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; bDivision of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea;cSong-dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; dDxome, Seoul, Republic of Korea; eDepartment of Laboratory Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea; fBrain Korea 21 PLUS Project for Medical Science,Yonsei University College of Medicine, Seoul, Republic of Korea.
*Address correspondence to: S.-T. L., S. Y. R.
†These authors contributed equally.
Abstract
Background
Ultra-deep sequencing to detect low-frequency mutations in circulating tumor-derived DNA (ctDNA) increases the diagnostic value of liquid biopsy. The demand for large ctDNA panels for comprehensive genomic profiling and tumor mutational burden (TMB) estimation is increasing; however, few ctDNA panels for TMB have been validated. Here, we designed a ctDNA panel with 531 genes, named TMB500, along with a technical and clinical validation.
Methods
Synthetic reference cell-free DNA materials with predefined allele frequencies were sequenced in a total of 92 tests in 6 batches to evaluate the precision, linearity, and limit of detection of the assay. We used clinical samples from 50 patients with various cancers, 11 healthy individuals, and paired tissue samples. Molecular barcoding and data analysis were performed using customized pipelines.
Results
The assay showed high precision and linearity (coefficient of determination, r2 = 0.87) for all single nucleotide variants, with a limit of detection of 0.24%. In clinical samples, the TMB500 ctDNA assay detected most variants present and absent in tissues, showing that ctDNA could assess tumor heterogeneity in different tissues and metastasis sites. The estimated TMBs correlated well between tissue and blood, except in 4 cases with extreme heterogeneity that showed very high blood TMBs compared to tissue TMBs. A pilot evaluation showed that the TMB500 assay could be used for disease monitoring.
Conclusions
The TMB500 assay is an accurate and reliable ctDNA assay for many clinical purposes. It may be useful for guiding the treatment of cancers with diverse genomic profiles, estimating TMB in immune therapy, and disease monitoring.
논문정보
- Research article
- 2022년 10월 (BRIC 등록일 2022-11-01)
- 국내 연구진
- 의약학 > 응용의학
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