NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

O'Cathail, S. M. , Wu, C.-H., Lewis, A., Holmes, C., Hawkins, M. A. and Maughan, T. (2020) NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer. Cancer Genetics, 248, pp. 1-10. (doi: 10.1016/j.cancergen.2020.08.006) (PMID:32871287)

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We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer. Background: NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights. Methods: Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms. Results: 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2–2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086–1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06–1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04–1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particularly enriched in Consensus Molecular Subtype (CMS) 4. Conclusion: For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study.

Item Type:Articles
Additional Information:The authors acknowledge the support of the UK Medical Research Council and Cancer Research UK stratified medicine consortium for colorectal cancer (S:CORT) in relation to collection, processing and quality control of the FOCUS trial samples, funding of CHW, and also the patients who participated in the trial. SMO'C is supported by CRUK (grant numbers H3R00390.H376; CAN-RES-UK (C7932/A25142)). MAH is funded by Medical Research Council (grant number MC/PC/12001/2). Annabelle Lewis is supported by MRC (MR/P000738/1). CCH is supported by the Medical Research Council, the EPSRC, the Alan Turing Institute and the Li Ka Shing Centre for Health Innovation and Discovery. Aspects of this work have been presented in abstract form at ASCO GI 2019 symposium.
Glasgow Author(s) Enlighten ID:O'Cathail, Dr Sean
Creator Roles:
O'Cathail, S.Conceptualization, Methodology, Resources, Writing – original draft, Writing – review and editing
Authors: O'Cathail, S. M., Wu, C.-H., Lewis, A., Holmes, C., Hawkins, M. A., and Maughan, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Genetics
ISSN (Online):2210-7770
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Cancer Genetics248:1-10
Publisher Policy:Reproduced under a Creative Commons license

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