A clonal expression biomarker associates with lung cancer mortality

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperLetterResearchpeer-review

  • Dhruva Biswas, UCL, The Francis Crick Institute
  • ,
  • Nicolai J. Birkbak
  • Rachel Rosenthal, UCL, The Francis Crick Institute
  • ,
  • Crispin T. Hiley, UCL, The Francis Crick Institute
  • ,
  • Emilia L. Lim, UCL, The Francis Crick Institute
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  • Krisztian Papp, Eötvös Loránd University
  • ,
  • Stefan Boeing, The Francis Crick Institute
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  • Marcin Krzystanek, Danish Cancer Society
  • ,
  • Dijana Djureinovic, Uppsala universitet
  • ,
  • Linnea La Fleur, Uppsala universitet
  • ,
  • Maria Greco, The Francis Crick Institute
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  • Balázs Döme, Semmelweis University, Medical University of Vienna
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  • János Fillinger, Semmelweis University, National Institute of Oncology
  • ,
  • Hans Brunnström, Lund University
  • ,
  • Yin Wu, UCL
  • ,
  • David A. Moore, University College London
  • ,
  • Marcin Skrzypski, UCL, Medical University of Gdansk
  • ,
  • Christopher Abbosh, UCL
  • ,
  • Kevin Litchfield, The Francis Crick Institute
  • ,
  • Maise Al Bakir, The Francis Crick Institute
  • ,
  • Thomas B.K. Watkins, The Francis Crick Institute
  • ,
  • Selvaraju Veeriah, UCL
  • ,
  • Gareth A. Wilson, UCL, The Francis Crick Institute
  • ,
  • Mariam Jamal-Hanjani, UCL
  • ,
  • Judit Moldvay, Semmelweis University
  • ,
  • Johan Botling, Uppsala universitet
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  • Arul M. Chinnaiyan, University of Michigan, Ann Arbor, Michigan.
  • ,
  • Patrick Micke, Uppsala universitet
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  • Allan Hackshaw, UCL
  • ,
  • Jiri Bartek, Danish Cancer Society, Karolinska Institutet
  • ,
  • Istvan Csabai, Eötvös Loránd University
  • ,
  • Zoltan Szallasi, Danish Cancer Society, Semmelweis University, Boston Children's Hospital
  • ,
  • Javier Herrero, UCL
  • ,
  • Nicholas McGranahan, UCL
  • ,
  • Charles Swanton, UCL, The Francis Crick Institute
  • ,
  • TRACERx Consortium

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 stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2–6. 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.

Original languageEnglish
JournalNature Medicine
Volume25
Issue10
Pages (from-to)1540-1548
Number of pages9
ISSN1078-8956
DOIs
Publication statusPublished - 2019

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