Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK.
Nat Commun. 2024 Sep 4;15(1):7731. doi: 10.1038/s41467-024-51577-2.
Whole genome sequencing (WGS) provides comprehensive, individualised cancer genomic information. However, routine tumour biopsies are formalin-fixed and paraffin-embedded (FFPE), damaging DNA, historically limiting their use in WGS. Here we analyse FFPE cancer WGS datasets from England's 100,000 Genomes Project, comparing 578 FFPE samples with 11,014 fresh frozen (FF) samples across multiple tumour types. We use an approach that characterises rather than discards artefacts. We identify three artefactual signatures, including one known (SBS57) and two previously uncharacterised (SBS FFPE, ID FFPE), and develop an "FFPEImpact" score that quantifies sample artefacts. Despite inferior sequencing quality, FFPE-derived data identifies clinically-actionable variants, mutational signatures and permits algorithmic stratification. Matched FF/FFPE validation cohorts shows good concordance while acknowledging SBS, ID and copy-number artefacts. While FF-derived WGS data remains the gold standard, FFPE-samples can be used for WGS if required, using analytical advancements developed here, potentially democratising whole cancer genomics to many.
全基因组测序（WGS）提供全面的、个体化的癌症基因组信息。然而，常规的肿瘤活检是福尔马林固定和石蜡包埋（FFPE）的，会破坏 DNA，这在历史上限制了它们在 WGS 中的应用。在这里，我们分析了来自英国的 100,000 基因组计划的 FFPE 癌症 WGS 数据集，比较了 578 个 FFPE 样本和 11014 个新鲜冷冻（FF）样本，涉及多种肿瘤类型。我们使用了一种能够描述而不是丢弃伪影的方法。我们确定了三个伪影特征，包括一个已知的（SBS57）和两个以前未被描述的（SBS FFPE、ID FFPE），并开发了一个“FFPEImpact”评分，用于量化样本伪影。尽管测序质量较差，但 FFPE 衍生的数据可以识别出具有临床意义的变异、突变特征，并允许算法分层。匹配的 FF/FFPE 验证队列显示出良好的一致性，同时承认 SBS、ID 和拷贝数伪影。虽然 FF 衍生的 WGS 数据仍然是黄金标准，但如果需要，使用这里开发的分析进展，可以使用 FFPE 样本进行 WGS，这可能会使癌症全基因组学民主化，惠及更多人。
