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

作者：Roseweir Antonia K^*; Halcrow Elaine S; Chichilo Sergey; Powell Arfon G M T; McMillan Donald C; Horgan Paul G; Edwards Joanne

来源：British Journal of Cancer, 2018, 119(3): 323-329.

DOI：10.1038/s41416-018-0174-y

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.

• 出版日期2018-8-1