Academic Unit of Surgery, School of Medicine-University of Glasgow, Royal Infirmary, Glasgow, G4 OSF, UK.
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Glasgow, G61 1QH, UK.
Br J Cancer. 2018 Aug;119(3):323-329. doi: 10.1038/s41416-018-0174-y. Epub 2018 Jul 10.
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.
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).
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).
MMR-competent stage III tumours harbouring BRAF mutations have an improved prognosis when strong nuclear phosphorylation of both ERK and p38MAPK is present.
在结直肠癌（CRC）中，BRAF 突变影响肿瘤进展。在错配修复缺陷（dMMR）肿瘤中，BRAF 突变与良好的预后相关，而在 MMR 功能正常的肿瘤中，BRAF 突变则是不利的。下游 MAPK 通路成员的差异表达，这些成员在 BRAF 突变患者中被持续激活，可能解释了这些差异。
使用 CRC 组织微阵列，通过免疫组织化学评估 ERK、p38MAPK 和 JNK 的磷酸化。对一个发现队列（n=187）和一个验证队列（n=801）进行分析，以确定与 BRAF 突变、临床病理特征和癌症特异性生存（CSS）的关联。
在 801 例 CRC 患者中，核 ERK 磷酸化（HR 0.65，95%CI 0.48-0.88，p=0.004）和核 pERK/p-p38 评分的联合（HR 0.61，95%CI 0.45-0.82，p=0.001）与 CSS 独立相关，并且与 BRAF 突变的增加进一步相关（p=0.003 和 p=0.002）。当按 BRAF 状态分层时，只有 MMR 功能正常的患者携带突变且有强烈的核 pERK/p-p38 评分（HR 0.49，95%CI 0.27-0.89，p=0.016），显示出更好的 CSS。CSS 的这种改善仅对 III 期 CRC 有特异性（HR 0.25，95%CI 0.10-0.64，p=0.002）。
当 ERK 和 p38MAPK 的核磷酸化均较强时，携带 BRAF 突变的 MMR 功能正常的 III 期肿瘤具有更好的预后。
