ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer

Roseweir, A. K. , Halcrow, E. S., Chichilo, S., Powell, A. G.M.T., McMillan, D. C. , Horgan, P. G. and Edwards, J. (2018) ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer. British Journal of Cancer, 119, pp. 323-329. (doi: 10.1038/s41416-018-0174-y) (PMID:29988110) (PMCID:PMC6070918)

163907.pdf - Accepted Version



Background In colorectal cancer (CRC), BRAF mutations influence tumour progression. In mismatch repair-deficient (dMMR) tumours, BRAF mutations are associated with a good prognosis, whereas in MMR-competent tumours, they are detrimental. The differential expression of the downstream MAPK pathway members, which are constitutively activated in BRAF mutant patients, may account for these differences. Methods Phosphorylation of ERK, p38MAPK and JNK was assessed by immunohistochemistry, utilising CRC tissue microarrays. A discovery cohort (n = 187) and a validation cohort (n = 801) were analysed for associations with BRAF mutations, clinicopathological characteristics and cancer-specific survival (CSS). Results In 801 CRC patients, nuclear ERK phosphorylation (HR 0.65 95% CI 0.48–0.88, p = 0.004) and the combined nuclear pERK/p-p38 score (HR 0.61 95% CI 0.45–0.82, p = 0.001) were independently associated with CSS, and were further associated with increased BRAF mutations (p = 0.003 and p = 0.002). When stratified for BRAF status, only MMR-competent patients harbouring the mutation and a strong combined nuclear pERK/p-p38 score (HR 0.49 95% CI 0.27–0.89, p = 0.016) demonstrated improved CSS. This improvement in CSS was specific to stage III CRC (HR 0.25 95% CI 0.10–0.64, p = 0.002). Conclusions MMR-competent stage III tumours harbouring BRAF mutations have an improved prognosis when strong nuclear phosphorylation of both ERK and p38MAPK is present.

Item Type:Articles
Additional Information:The Hugh Fraser Non-Clinical Lecturer in Surgery Fellowship and The Royal College of Physicians and Surgeons of Glasgow Ritchie Trust Fellowship supported this work.
Glasgow Author(s) Enlighten ID:Edwards, Professor Joanne and Horgan, Professor Paul and Roseweir, Dr Antonia and McMillan, Professor Donald
Authors: Roseweir, A. K., Halcrow, E. S., Chichilo, S., Powell, A. G.M.T., McMillan, D. C., Horgan, P. G., and Edwards, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:British Journal of Cancer
Publisher:Springer Nature
ISSN (Online):1532-1827
Copyright Holders:Copyright © 2018 Cancer Research UK
First Published:First published in British Journal of Cancer 119:323-329
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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