Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, London, UK.
Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O'Gorman Building, London, UK.
Nat Med. 2019 Oct;25(10):1540-1548. doi: 10.1038/s41591-019-0595-z. Epub 2019 Oct 7.
An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.
分子生物标志物的一个目标是将癌症患者分为具有预测预后的疾病亚型，从而提高诊断精度，超越肿瘤分期等临床描述。转录组肿瘤内异质性（RNA-ITH）已被证明会混淆多种癌症类型中现有的基于表达的生物标志物。在这里，我们分析了 TRACERx 研究中 48 名患者的 156 个肿瘤区域的多区域全外显子组和 RNA 测序数据，以探索和控制非小细胞肺癌中的 RNA-ITH。我们发现染色体不稳定性是 RNA-ITH 的主要驱动因素，并且现有的预后基因表达特征容易受到肿瘤取样偏差的影响。为了解决这个问题，我们确定了在单个肿瘤内均匀表达的基因，这些基因编码癌症细胞增殖的表达模块，并且通常由肿瘤进化早期选择的 DNA 拷贝数增益驱动。克隆转录组生物标志物克服了肿瘤取样偏差，与临床病理危险因素无关的生存相关，并且可能为跨癌症类型改进生物标志物设计提供一种通用策略。
