期刊
NATURE MEDICINE
卷 25, 期 10, 页码 1540-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0595-z
关键词
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资金
- MBPhD program at University College London
- NIHR BRC at University College London Hospitals
- Aarhus University Research Foundation
- Danish Cancer Society
- Hungarian Science Foundation [OTKA-K129065]
- Breast Cancer Research Foundation [BCRF-18-159]
- Wellcome Trust [FC001169]
- Royal Society [211179/Z/18/Z]
- Cancer Research UK (CRUK)
- Rosetrees
- Royal Society Napier Research Professor
- Francis Crick Institute
- Cancer Research UK
- UK Medical Research Council [FC001169, MR/P014712/1]
- CRUK Cancer Immunotherapy Catalyst Network
- CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C)
- Rosetrees Trust
- Stoneygate Trusts
- NovoNordisk Foundation [ID16584]
- Prostate Cancer Foundation
- Breast Cancer Research Foundation (BCRF)
- European Research Council (ERC) [FP7-THESEUS-617844]
- European Commission ITN [607722]
- ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union [835297]
- National Institute for Health Research
- University College London Hospitals Biomedical Research Centre
- Cancer Research UK University College London Experimental Cancer Medicine Centre
- [NVKP_16-1-2016-0004]
- [NAP2-2017-1.2.1-NKP-0002]
- MRC [MR/M009033/1, MR/P014712/1] Funding Source: UKRI
- The Francis Crick Institute [10233] Funding Source: researchfish
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(1). Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types(2-6). 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.
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