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. 2025 Aug 14;31(16):3512-3525.
doi: 10.1158/1078-0432.CCR-24-2188.

A Concordance Study among 26 NGS Laboratories Participating in the NCI Molecular Analysis for Therapy Choice Clinical Trial

Linda K Zane  1 , Laura M Yee  1 , Ting-Chia Chang  2 , Jeffrey Sklar  3 , Guangxiao Yang  3 , Jia Di Wen  3 , Peining Li  3 , Robin Harrington  2 , David J Sims  2 , Kneshay Harper  2 , Jeffrey M Trent  4 , Janine R LoBello  4 , Szabolcs Szelinger  4 , Kasey Benson  5 , Jia Zeng  5 , Kelsey Poorman  5 , Danbin Xu  6 , Garrett M Frampton  7 , Dean C Pavlick  7 , Vincent A Miller  7 , Bevan Tandon  8 , Wojciech Swat  8 , Lawrence Weiss  9 , Vincent Anthony Funari  9 , Jeffrey M Conroy  10 , James L Prescott  11 , Pranil K Chandra  11 , Charles Ma  12 , Kristen J Champion  12 , Gregory X Baschkopf  12 , Yuri A Fesko  12 , Tracey Allen K Freitas  12 , Scott A Tomlins  13 , Daniel H Hovelson  13 , Kevin White  14 , Shelly Sorrells  14 , Robert Tell  14 , Nike Beaubier  14 , David King  14 , Lei Li  15 , Kevin Kelly  15 , Jasmina Uvalic  15 , Bridgette Meyers  15 , Ravindra Kolhe  16 , Neal I Lindeman  17 , Michele Baltay  17 , Lynette M Sholl  18 , Jean Lopategui  18 , Eric Vail  18 , Wenjuan Zhang  18 , Milhan Telatar  19 , Michelle Afkhami  19 , Susan J Hsiao  20 , Mahesh M Mansukhani  20 , Emily Adams  21 , LiQun Jiang  21 ; NCI-MATCH Designated Laboratories; Kenneth D Aldape  22 , Mark Raffeld  22 , Liqiang Xi  22 ; for NCI-COMPASS Team; Henning Stehr  23 , Jeremy P Segal  24 , Dara L Aisner  25 , Kurtis D Davies  25 , Noah A Brown  26 , Robert J Livingston  27 , Eric Q Konnick  28 , Wei Song  28 , James P Solomon  28 , Zenta Walther  29 ; for NCI-MATCH Designated Laboratories; Lisa M McShane  1 , Lyndsay N Harris  1 , Alice P Chen  1 , Gregory J Tsongalis  30 , Stanley R Hamilton  31 , Keith T Flaherty  32 , Peter J O'Dwyer  33 , Barbara A Conley  1 , David R Patton  1 , A John Iafrate  34 , P Mickey Williams  2 , James V Tricoli #  1 , Chris Karlovich #  2
Affiliations

A Concordance Study among 26 NGS Laboratories Participating in the NCI Molecular Analysis for Therapy Choice Clinical Trial

Linda K Zane et al. Clin Cancer Res. .

Abstract

Purpose: NCI selected a network of Clinical Laboratory Improvement Amendments-certified laboratories performing routine next-generation sequencing (NGS) tumor testing to identify patients for the NCI Molecular Analysis for Therapy Choice (NCI-MATCH) trial. This large network provided a unique opportunity to compare variant detection and reporting between a wide range of testing platforms.

Experimental design: Twenty-eight NGS assays from 26 laboratories within the NCI-MATCH Network, including the NCI-MATCH central laboratory (CL) and 11 commercial and 14 academic designated laboratories (DL), were used for this study. DNA from eight cell lines and two clinical samples were sequenced. Pairwise comparisons in variant detection and reporting between each DL and CL were performed for single-nucleotide variant, insertion and deletion, and copy-number variant classes.

Results: We observed high concordance in variant detection between CL and DL for single-nucleotide variants and insertions and deletions [average positive agreement (APA) > 95.4% for all pairwise comparisons] but lower concordance for variant reporting after analysis pipeline filtering. We observed much higher agreement between CL and assays using amplification as the target enrichment method (84.2% < APA ≤ 95.7%, average APA = 88.7%) than other assays using hybridization capture (69.7% < APA ≤ 93.8%, average APA = 77.4%) due to blacklisting of actionable variants in low complexity regions. For copy-number variant reporting, we observed high agreement (APA > 82%) except between CL and two assays (APA = 76.9% and 71.4%) due to differences in estimation of copy numbers. Notably, for all variants, differences in variant interpretation also contributed to reporting discrepancies.

Conclusions: This study indicates that different NGS tumor profiling tests currently in widespread clinical use achieve high concordance between assays in variant detection. For variant reporting, observed discrepancies are mainly introduced during the bioinformatic analysis.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

A. John Iafrate reports receiving royalties from Invitae and being a scientific advisory board member for Kinnate, Repare, SequreDx and Paige.AI. No potential conflicts of interest were disclosed by the other authors.

The views presented in this article are those of the authors and should not be viewed as official opinions or positions of the National Cancer Institute, NIH, or U.S. Department of Health and Human Services.

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