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A clonal expression biomarker associates with lung cancer mortality

Biswas, Dhruva ; Birkbak, Nicolai J. ; Rosenthal, Rachel ; Hiley, Crispin T. ; Lim, Emilia L. ; Papp, Krisztian ; Boeing, Stefan ; Krzystanek, Marcin ; Djureinovic, Dijana and La Fleur, Linnea , et al. (2019) In Nature Medicine 25(10). p.1540-1548
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 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... (More)

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.

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type
Contribution to journal
publication status
published
subject
in
Nature Medicine
volume
25
issue
10
pages
9 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85074193009
  • pmid:31591602
ISSN
1078-8956
DOI
10.1038/s41591-019-0595-z
language
English
LU publication?
yes
id
425ddb85-2351-4c76-859b-a2fc61ede68a
date added to LUP
2019-11-06 09:33:03
date last changed
2024-04-02 19:15:35
@article{425ddb85-2351-4c76-859b-a2fc61ede68a,
  abstract     = {{<p>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<sup>1</sup>. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types<sup>2–6</sup>. 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.</p>}},
  author       = {{Biswas, Dhruva and Birkbak, Nicolai J. and Rosenthal, Rachel and Hiley, Crispin T. and Lim, Emilia L. and Papp, Krisztian and Boeing, Stefan and Krzystanek, Marcin and Djureinovic, Dijana and La Fleur, Linnea and Greco, Maria and Döme, Balázs and Fillinger, János and Brunnström, Hans and Wu, Yin and Moore, David A. and Skrzypski, Marcin and Abbosh, Christopher and Litchfield, Kevin and Al Bakir, Maise and Watkins, Thomas B.K. and Veeriah, Selvaraju and Wilson, Gareth A. and Jamal-Hanjani, Mariam and Moldvay, Judit and Botling, Johan and Chinnaiyan, Arul M. and Micke, Patrick and Hackshaw, Allan and Bartek, Jiri and Csabai, Istvan and Szallasi, Zoltan and Herrero, Javier and McGranahan, Nicholas and Swanton, Charles}},
  issn         = {{1078-8956}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{1540--1548}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Medicine}},
  title        = {{A clonal expression biomarker associates with lung cancer mortality}},
  url          = {{http://dx.doi.org/10.1038/s41591-019-0595-z}},
  doi          = {{10.1038/s41591-019-0595-z}},
  volume       = {{25}},
  year         = {{2019}},
}