The benefit of a complete reference genome for cancer structural variant analysis.
The benefit of a complete reference genome for cancer structural variant analysis.
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完整参考基因组对癌症结构变异分析的好处。
DOI：
10.1101/2024.03.15.24304369
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Sedlazeck,FritzJ
中科院分区：
文献类型：
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作者：
Paulin,LuisF;Fan,Jeremy;O'Neill,Kieran;Pleasance,Erin;Porter,VanessaL;Jones,StevenJM;Sedlazeck,FritzJ
由于测序技术的进步和生物信息学分析的改进，癌症基因组的复杂性变得越来越容易解释。结构变异体（SV）代表了肿瘤中体细胞事件的一个重要子集。虽然SV的检测已经通过长读段测序的发展而显著改善，但体细胞变体鉴定和注释仍然具有挑战性。我们假设使用完整的人参考基因组（CHM 13-T2 T）将改善体细胞SV呼叫。我们在肿瘤/正常匹配的基准样本和两个患者样本中的发现表明，与GRCh 38相比，CHM 13-T2 T提高了SV检测和优先级排序的准确性，假阳性呼叫显著减少。我们还通过将CHM 13-T2 T比对的读段提升到GRCh 38基因组来克服CHM 13-T2 T的注释资源的缺乏，因此结合了改进的比对和高级注释。在此过程中，我们评估了COLO 829/COLO 829 BL的当前SV基准集，包括在不同中心使用不同长读技术测序的四个重复。我们发现该细胞系在这些重复中不稳定; 346个SV（1.13%）仅在单次重复中可重复。我们确定了49个体细胞SV，它们似乎是稳定的，因为它们在四个重复中一致存在。因此，我们提出这个共识集作为体细胞SV调用的更新基准，并在我们的基准中包括GRCh 38和CHM 13-T2 T坐标。该基准可在以下网址获得：10.5281/zenodo.10819636我们的工作展示了优化癌症中体细胞SV优先级的新方法，并在其他遗传疾病中具有潜在的改善。
The complexities of cancer genomes are becoming more easily interpreted due to advancements in sequencing technologies and improved bioinformatic analysis. Structural variants (SVs) represent an important subset of somatic events in tumors. While detection of SVs has been markedly improved by the development of long-read sequencing, somatic variant identification and annotation remains challenging. We hypothesized that use of a completed human reference genome (CHM13-T2T) would improve somatic SV calling. Our findings in a tumour/normal matched benchmark sample and two patient samples show that the CHM13-T2T improves SV detection and prioritization accuracy compared to GRCh38, with a notable reduction in false positive calls. We also overcame the lack of annotation resources for CHM13-T2T by lifting over CHM13-T2T-aligned reads to the GRCh38 genome, therefore combining both improved alignment and advanced annotations. In this process, we assessed the current SV benchmark set for COLO829/COLO829BL across four replicates sequenced at different centers with different long-read technologies. We discovered instability of this cell line across these replicates; 346 SVs (1.13%) were only discoverable in a single replicate. We identify 49 somatic SVs, which appear to be stable as they are consistently present across the four replicates. As such, we propose this consensus set as an updated benchmark for somatic SV calling and include both GRCh38 and CHM13-T2T coordinates in our benchmark. The benchmark is available at: 10.5281/zenodo.10819636 Our work demonstrates new approaches to optimize somatic SV prioritization in cancer with potential improvements in other genetic diseases.