Lakbir Soufyan, de Wit Renske, de Bruijn Ino, Kundra Ritika, Madupuri Ramyasree, Gao Jianjiong, Schultz Nikolaus, Meijer Gerrit A, Heringa Jaap, Fijneman Remond J A, Abeln Sanne
Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
NPJ Precis Oncol. 2025 May 14;9(1):140. doi: 10.1038/s41698-025-00922-9.
While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.
虽然结构变异（SVs）是基因组不稳定的明显标志，但由于成本下降直到最近才使得大规模分析成为可能，此前尚未对每位患者的SVs进行系统量化。因此，患者体内大量SVs的生物学和临床影响尚不清楚。我们引入肿瘤断裂负荷（TBL），定义为不平衡SVs的总和，作为衡量与SV相关的基因组不稳定的指标。利用来自TCGA、PCAWG和CCLE的泛癌数据，我们发现，在31种癌症类型中的26种中，高TBL与基因表达的显著变化相关，这些变化一致地涉及DNA损伤修复的上调和免疫反应途径的下调。TBL高的患者在15种癌症类型中的5种中显示出更高的复发风险和更短的中位生存时间。我们的数据表明，TBL是基因组不稳定的一个生物学和临床相关特征，可能有助于患者的预后评估和治疗分层。对于本研究中分析的数据集，TBL已在cBioPortal中提供。
