BRAF and KRAS mutations in mismatch repair deficient colorectal cancer

Abstract

Activation of the RAS-RAF-MEK-ERK-MAP kinase pathway plays an important role in colorectal carcinogenesis. We have recently reported the occurrence of BRAF mutation in a small proportion of colorectal cancers and adenomas, and in a high proportion of hyperplastic polyps and serrated adenomas (Cancer Res 2002, 62:6451; Cancer Res 2003, 63:4878). Moreover, the incidence of BRAF mutation was reported to be higher in microsatellite unstable (MSI-H) colorectal cancers. In an ongoing study of more than 500 colorectal cancers, we identified 87 MSI-H tumours. Here we studied these 87 MSI-H colorectal cancers for BRAF and KRAS mutations and examined their relationships with the status of mismatch repair proteins expression, age of onset and hMLH1 promoter methylation status. BRAF and KRAS mutations were identified in 10 (11.5%) and 30 (34.5%) cases respectively. Nine out of 10 BRAF mutations were V599E, the previously described hotspot, and none of these was associated with KRAS mutation. BRAF mutation was found mostly in cancers with hMLH1 protein loss (9 out of 47) and rarely in cancers with hMSH2 loss, hMSH6 loss or no protein loss (1 out of 40)(p=0.037). All 10 cases with BRAF mutation were found in patients aged >50 (n=39), and none was found in patients aged below 50 (p=0.006). No such relationship was found for KRAS mutation. Furthermore, amongst cases with hMLH1 protein loss, BRAF mutation was found exclusively in cases with hMLH1 promoter methylation. (p=0.023). The selective association of BRAF mutation with late-onset MSI-H colorectal cancer with hMLH1 promoter methylation, and its previously reported high incidence in hyperplastic polyps and serrated adenomas, suggest that this group of cancer may have evolved from the serrated neoplasia pathway.