Purpose: To design a pan-cancer gene panel for childhood malignancies and validate it using clinically characterized patient samples. Experimental Design: In addition to 5,275 coding exons, SJPedPanel also covers 297 introns for fusions/structural variations and 7,590 polymorphic sites for copy number alterations. Capture uniformity and limit of detection are determined by targeted sequencing of cell lines using dilution experiment. We validate its coverage by in silico analysis of an established real-time clinical genomics (RTCG) cohort of 253 patients. We further validate its performance by targeted re-sequencing of 113 patient samples from the RTCG cohort. We demonstrate its power in analyzing low tumor burden specimens using morphologic remission and monitoring samples. Results: Among the 485 pathogenic variants reported in RTCG cohort, SJPedPanel covered 86% of variants, including 82% of 90 rearrangements responsible for fusion oncoproteins. In our targeted re-sequencing cohort, 91% of 389 pathogenic variants are detected. The gene panel enabled us to detect ~95% of variants at allele fraction 0.5%, while the detection rate is ~80% at allele fraction 0.2%. The panel detected low frequency driver alterations from morphologic leukemia remission samples and relapse-enriched alterations from monitoring samples, demonstrating its power for cancer monitoring and early detection. Conclusions: SJPedPanel enables the cost-effective detection of clinically relevant genetic alterations including rearrangements responsible for subtype-defining fusions by targeted sequencing of ~0.15% of human genome for childhood malignancies. It will enhance the analysis of specimens with low tumor burdens for cancer monitoring and early detection.

中文翻译：

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SJPedPanel：针对儿童恶性肿瘤的泛癌基因组，以加强癌症监测和早期发现


目的：设计针对儿童恶性肿瘤的泛癌基因组，并使用临床特征的患者样本对其进行验证。实验设计：除了 5,275 个编码外显子外，SJPedPanel 还涵盖 297 个用于融合/结构变异的内含子和 7,590 个用于拷贝数改变的多态性位点。捕获均匀性和检测限通过使用稀释实验对细胞系进行靶向测序来确定。我们通过对已建立的 253 名患者的实时临床基因组学 (RTCG) 队列进行计算机分析来验证其覆盖范围。我们通过对 RTCG 队列中的 113 名患者样本进行有针对性的重新测序来进一步验证其性能。我们证明了它在使用形态学缓解和监测样本分析低肿瘤负荷标本方面的能力。结果：在 RTCG 队列中报告的 485 个致病变异中，SJPedPanel 覆盖了 86% 的变异，包括导致融合癌蛋白的 90 个重排中的 82%。在我们的目标重测序队列中，检测到了 389 个致病变异中的 91%。基因组使我们能够检测到等位基因分数 0.5% 时约 95% 的变异，而等位基因分数 0.2% 时的检测率为约 80%。该小组从形态学白血病缓解样本中检测到低频驱动改变，并从监测样本中检测到复发丰富的改变，证明了其在癌症监测和早期检测方面的能力。结论：SJPedPanel 通过对儿童恶性肿瘤约 0.15% 的人类基因组进行靶向测序，能够经济高效地检测临床相关的遗传改变，包括导致亚型定义融合的重排。它将增强对低肿瘤负荷样本的分析，以进行癌症监测和早期检测。