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

TitleCross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions.
Publication TypeJournal Article
Year of Publication2021
AuthorsGong, B, Li, D, Kusko, R, Novoradovskaya, N, Zhang, Y, Wang, S, Pabón-Peña, C, Zhang, Z, Lai, K, Cai, W, LoCoco, JS, Lader, E, Richmond, TA, Mittal, VK, Liu, L-C, Johann, DJ, Willey, JC, Bushel, PR, 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, ABergstrom, Best, H, Bhandari, A, Bisgin, H, Blackburn, J, Blomquist, TM, Boardman, L, Burgher, B, Butler, DJ, Chang, C-J, Chaubey, A, Chen, T, Chierici, M, Chin, CR, Close, D, Conroy, J, Coleman, JCooley, Craig, DJ, Crawford, E, Del Pozo, A, Deveson, IW, Duncan, D, Eterovic, AKarina, 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, DPhilip, Łabaj, P, Lapunzina, P, Li, P, Li, Q-Z, Li, W, Li, Z, Liang, Y, Liu, S, Liu, Z, Ma, C, Marella, N, Martín-Arenas, R, Megherbi, DB, Meng, Q, Mieczkowski, PA, Morrison, T, Muzny, DM, Ning, B, Parsons, BL, Paweletz, CP, 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, JCarlos, Smith, M, López, MSolís, 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, VJ, Thomas, D, Tichý, B, Tom, N, Garcia, EVallespin, 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, SH, Zhang, G, Zhang, S, Zhao, M, Zheng, Y, Zhou, X, Mason, CE, Mercer, T, Tong, W, Shi, L, Jones, W, Xu, J
JournalGenome Biol
Date Published2021 Apr 16
KeywordsBiomarkers, Tumor, DNA Copy Number Variations, Genetic Testing, Genomics, Humans, Molecular Diagnostic Techniques, Mutation, Neoplasms, Oncogenes, Polymorphism, Single Nucleotide, Reproducibility of Results, Sensitivity and Specificity

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.

Alternate JournalGenome Biol
PubMed ID33863344
PubMed Central IDPMC8051090
Grant ListR15 GM114739 / GM / NIGMS NIH HHS / United States
E0767001 / / U.S. Food and Drug Administration /
E0765001 / / U.S. Food and Drug Administration /
P30 CA015083 / CA / NCI NIH HHS / United States
R15 GM137288 / GM / NIGMS NIH HHS / United States

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