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A clonal expression biomarker associates with lung cancer mortality

Item Type:Article
Title:A clonal expression biomarker associates with lung cancer mortality
Creators Name:Biswas, D. and Birkbak, N.J. and Rosenthal, R. and Hiley, C.T. and Lim, E.L. and Papp, K. and Boeing, S. and Krzystanek, M. and Djureinovic, D. and La Fleur, L. and Greco, M. and Döme, B. and Fillinger, J. and Brunnström, H. and Wu, Y. and Moore, D.A. and Skrzypski, M. and Abbosh, C. and Litchfield, K. and Al Bakir, M. and Watkins, T.B.K. and Veeriah, S. and Wilson, G.A. and Jamal-Hanjani, M. and Moldvay, J. and Botling, J. and Chinnaiyan, A.M. and Micke, P. and Hackshaw, A. and Bartek, J. and Csabai, I. and Szallasi, Z. and Herrero, J. and McGranahan, N. and Swanton, C.
Abstract: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 (RNAITH) 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.
Keywords:Clonal Evolution, DNA Copy Number Variations, Disease-Free Survival, Exome, Genetic Heterogeneity, Lung Neoplasms, Neoplastic Gene Expression Regulation, Prognosis, Risk Factors, Transcriptome, Tumor Biomarkers, Whole Exome Sequencing
Source:Nature Medicine
Publisher:Nature Publishing Group
Page Range:1540-1548
Date:October 2019
Additional Information:Roland Schwarz is a member of the TRACERx Consortium. Erratum in Nat Med. 2020 Jul;26(7):1148
Official Publication:https://doi.org/10.1038/s41591-019-0595-z
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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