Séan M O'Cathail1, Chieh-Hsi Wu2, Annabelle Lewis3, Chris Holmes4, Maria A Hawkins5, Tim Maughan6. 1. Institute of Cancer Sciences, University of Glasgow, United Kingdom. Electronic address: Sean.OCathail@glasgow.ac.uk. 2. Department of Statistics, University of Southampton, United Kingdom. 3. Department of Life science, CHMLS, Brunel University London, United Kingdom. 4. Department of Statistics, University of Southampton, United Kingdom; Nuffield Department of Medicine, University of Oxford, United Kingdom; Alan Turing Institute, London, United Kingdom. 5. University College London, United Kingdom. 6. Oxford Institute of Radiation Oncology, University of Oxford, United Kingdom.
Abstract
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.
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.
Authors: Séan M O'Cathail; Chieh-Hsi Wu; Rachael Thomas; Maria A Hawkins; Tim S Maughan; Annabelle Lewis Journal: Antioxidants (Basel) Date: 2021-08-28