Abstract 5366: DRAGEN pipeline validation for somatic variant detection in diagnostics using TSO500 panel

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Abstract Background: The DRAGEN pipeline has recently been released for the analysis of whole genome and exome sequencing data (PMID:39455800). However, its performance in detecting clinically relevant alterations for routine diagnostic practice remains unknown. Methods: This study includes 108 lung cancer patients consecutively collected from the TNM-I trial (NCT03299478). Tumor-only sequencing of FFPE DNA was performed using the TruSight Oncology 500 (TSO500) panel. Alignment and variant calling were conducted with DRAGEN (TSO500 v2.5.2) and Mutect2-GATK (v2.2), with subsequent annotation and classification using PCGR (v2.1.2) and OncoKB (v3.4.1). Results: In the DRAGEN pipeline output, 4328 exonic and nonsynonymous variants with a variant allele fraction (VAF) >0.01 and a minimum supporting read count of 5 (normalized by depth) were analyzed. Among these, 214 variants met actionability tiers 1-3 (AMP/ASCO/CAP) and oncogenicity score >3 based on ClinGen/CGC/VICC Oncogenicity Guidelines, with the highest calls observed for TP53 (44%, n=48) and KRAS (34%, n=37). DRAGEN and Mutect2 showed 100% concordance in detecting level 1 variants (OncoKB classifications), distributed as follows: KRAS (16 variants), EGFR (2 variants), and BRAF (1 variant). The median VAF difference between the two pipelines was 0.017, indicating strong alignment in allele frequency for high-confidence variants. Additionally, 174 variants (84%) showed a VAF difference within ±3.0%, suggesting minor VAF calculation variability in a subset of cases. Across all matched variants, DRAGEN reported consistently lower read depth values than Mutect2, with a median depth of 275 for DRAGEN versus 375 for Mutect2. DRAGEN also demonstrated a lower standard deviation in read depth (188 vs. 320 for Mutect2), indicating tighter depth distribution. This depth discrepancy was particularly pronounced in variants with a >3% VAF difference, suggesting that depth differences may contribute to VAF variability between the pipelines. No level-2 OncoKB classifications were detected by either pipeline. Conclusion: These findings demonstrate DRAGEN concordance with GATK for detecting clinically significant Tier 1 variants, supporting its reliability in routine diagnostics despite read depth inconsistencies. Future studies should further explore DRAGEN performance in detecting copy number variants and fusion calls. Citation Format: Mehrdad Rakaee, Per Niklas Waaler, Falah Jabar, Krinio Giannikou, Elio Adib, Sigve Andersen, Erna-Elise Paulsen, Thomas K.Kilvaer, Elisabeth Jarhelle, Kristin Åberg, Espen Mikal Robertsen, Ane Yde Schmidt, Christina Westmose Yde, Christian Baudet, Åslaug Helland, Mette Pøhl, Lill-Tove R. Busund, David J. Kwiatkowski, Tom Donnem. DRAGEN pipeline validation for somatic variant detection in diagnostics using TSO500 panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5366.

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