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Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions

Abstract

BACKGROUND: Targeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing. RESULTS: All panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden. CONCLUSION: This comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.

Type Journal
ISBN 1474-760X (Electronic) 1474-7596 (Linking)
Authors Gong, B.; Li, D.; Kusko, R.; Novoradovskaya, N.; Zhang, Y.; Wang, S.; Pabon-Pena, C.; Zhang, Z.; Lai, K.; Cai, W.; LoCoco, J. S.; Lader, E.; Richmond, T. A.; Mittal, V. K.; Liu, L. C.; Johann, D. J., Jr.; Willey, J. C.; Bushel, P. R.; Yu, Y.; Xu, C.; Chen, G.; Burgess, D.; Cawley, S.; Giorda, K.; Haseley, N.; Qiu, F.; Wilkins, K.; Arib, H.; Attwooll, C.; Babson, K.; Bao, L.; Bao, W.; Lucas, A. B.; Best, H.; Bhandari, A.; Bisgin, H.; Blackburn, J.; Blomquist, T. M.; Boardman, L.; Burgher, B.; Butler, D. J.; Chang, C. J.; Chaubey, A.; Chen, T.; Chierici, M.; Chin, C. R.; Close, D.; Conroy, J.; Coleman, J. C.; Craig, D. J.; Crawford, E.; Del Pozo, A.; Deveson, I. W.; Duncan, D.; Eterovic, A. K.; Fan, X.; Foox, J.; Furlanello, C.; Ghosal, A.; Glenn, S.; Guan, M.; Haag, C.; Hang, X.; Happe, S.; Hennigan, B.; Hipp, J.; Hong, H.; Horvath, K.; Hu, J.; Hung, L. Y.; Jarosz, M.; Kerkhof, J.; Kipp, B.; Kreil, D. P.; Labaj, P.; Lapunzina, P.; Li, P.; Li, Q. Z.; Li, W.; Li, Z.; Liang, Y.; Liu, S.; Liu, Z.; Ma, C.; Marella, N.; Martin-Arenas, R.; Megherbi, D. B.; Meng, Q.; Mieczkowski, P. A.; Morrison, T.; Muzny, D.; Ning, B.; Parsons, B. L.; Paweletz, C. P.; Pirooznia, M.; Qu, W.; Raymond, A.; Rindler, P.; Ringler, R.; Sadikovic, B.; Scherer, A.; Schulze, E.; Sebra, R.; Shaknovich, R.; Shi, Q.; Shi, T.; Silla-Castro, J. C.; Smith, M.; Lopez, M. S.; Song, P.; Stetson, D.; Strahl, M.; Stuart, A.; Supplee, J.; Szankasi, P.; Tan, H.; Tang, L. Y.; Tao, Y.; Thakkar, S.; Thierry-Mieg, D.; Thierry-Mieg, J.; Thodima, V. J.; Thomas, D.; Tichy, B.; Tom, N.; Garcia, E. V.; Verma, S.; Walker, K.; Wang, C.; Wang, J.; Wang, Y.; Wen, Z.; Wirta, V.; Wu, L.; Xiao, C.; Xiao, W.; Xu, S.; Yang, M.; Ying, J.; Yip, S. H.; Zhang, G.; Zhang, S.; Zhao, M.; Zheng, Y.; Zhou, X.; Mason, C. E.; Mercer, T.; Tong, W.; Shi, L.; Jones, W.; Xu, J.
Responsible Garvan Author Dr Timothy Mercer
Publisher Name GENOME BIOLOGY
Published Date 2021-04-30
Published Volume 22
Published Issue 1
Published Pages 109
Status Published in-print
DOI 10.1186/s13059-021-02315-0
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/33863344