Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative forKRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative forKRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS).
However, African Americans with microsatellite stable (MSS)/MSI-low (MSI-L) tumors had a higher proportion of KRAS mutations than Caucasians (34% vs. 23%, P = 0.048) that was isolated to proximal colon cancers and primarily driven by mutations in codon 13.
The overall inverse association between folate and colon cancer did not differ significantly according to MSI status [relative ratio (RR), 0.79; 95% confidence interval (95% CI), 0.60-1.03 for microsatellite stable/MSI-low colon cancers; and RR, 0.61, 95% CI, 0.37-1.02 for MSI-high colon cancers; P(heterogeneity)=0.53] or KRAS status (RR, 0.66; 95% CI, 0.49-0.87 for KRAS wild-type colon cancers; and RR, 1.05; 95% CI, 0.68-1.61 for KRAS mutated colon cancers; P(heterogeneity)=0.12), although our analyses had limited power to preclude an effect of folate on KRAS wild-type colon cancers.
BRAF and KRAS mutation may initiate different pathways of senescence-associated serrated neoplasia in the colorectum, the former linked to CpG island methylator phenotype (CIMP)-high (CIMP1) and microsatellite instability (MSI)-high status and the latter with CIMP-low (CIMP2) and MSI-low status.