Most current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex rearrangements, heterogeneity, and aneuploidy. Here, we present Severus: a method for the accurate detection of different types of somatic SVs using a phased breakpoint graph approach. To benchmark various short- and long-read SV detection methods, we sequenced five tumor/normal cell line pairs with Illumina, Nanopore, and PacBio sequencing platforms; on this benchmark Severus showed the highest F1 scores (harmonic mean of the precision and recall) as compared to long-read and short-read methods. We then applied Severus to three clinical cases of pediatric cancer, demonstrating concordance with known genetic findings as well as revealing clinically relevant cryptic rearrangements missed by standard genomic panels.

中文翻译：

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Severus：使用长读长准确检测和表征肿瘤基因组中的体细胞结构变异

目前大多数研究依赖短读长测序来检测癌症基因组中的体细胞结构变异（SV）。长读长测序具有更好的可定位性和远程定相的优势，从而显着改善种系 SV 检测。然而，目前的长读长 SV 检测方法并不能很好地推广到具有复杂重排、异质性和非整倍性的肿瘤基因组中体细胞 SV 的分析。在这里，我们介绍 Severus：一种使用分阶段断点图方法准确检测不同类型体细胞 SV 的方法。为了对各种短读长和长读长 SV 检测方法进行基准测试，我们使用 Illumina、Nanopore 和 PacBio 测序平台对五对肿瘤/正常细胞系进行了测序；在此基准上，与长读和短读方法相比，Severus 显示了最高的 F1 分数（精确度和召回率的调和平均值）。然后，我们将 Severus 应用于三个儿科癌症的临床病例，证明了与已知遗传发现的一致性，并揭示了标准基因组组遗漏的临床相关的神秘重排。