Chukwu Wolu, Lee Siyun, Crane Alexander, Zhang Shu, Webster Sophie, Dakhama Oumayma, Mittra Ipsa, Rauert Carlos, Imielinski Marcin, Beroukhim Rameen, Dubois Frank, Dalin Simona
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cell Rep Methods. 2025 Mar 24;5(3):100991. doi: 10.1016/j.crmeth.2025.100991. Epub 2025 Mar 12.
Although several recent studies have characterized structural variants (SVs) in germline and cancer genomes independently, the genomic contexts of these SVs have not been comprehensively compared. We examined similarities and differences between 2 million germline and 115 thousand tumor SVs from a cohort of 963 patients from The Cancer Genome Atlas. We found significant differences in features related to their genomic sequences and localization that suggest differences between SV-generating processes and selective pressures. For example, our results show that features linked to transposon-mediated processes are associated with germline SVs, while somatic SVs more frequently show features characteristic of chromoanagenesis. These genomic differences enabled us to develop a classifier-the Germline and Tumor Structural Variant or "the great GaTSV" -that accurately distinguishes between germline and cancer SVs in tumor samples that lack a matched normal sample.
尽管最近有几项研究分别对生殖系和癌症基因组中的结构变异（SVs）进行了特征描述，但这些SVs的基因组背景尚未得到全面比较。我们研究了来自癌症基因组图谱（The Cancer Genome Atlas）的963名患者队列中的200万个生殖系SVs和11.5万个肿瘤SVs之间的异同。我们发现，与它们的基因组序列和定位相关的特征存在显著差异，这表明SV产生过程和选择压力之间存在差异。例如，我们的结果表明，与转座子介导过程相关的特征与生殖系SVs有关，而体细胞SVs更频繁地表现出染色体混乱的特征。这些基因组差异使我们能够开发一种分类器——生殖系和肿瘤结构变异分类器（Germline and Tumor Structural Variant，简称“伟大的GaTSV”），该分类器能够在缺乏匹配正常样本的肿瘤样本中准确区分生殖系SVs和癌症SVs。
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