Downregulation of p27 (
cyclin-dependent kinase inhibitor-1B, CDKN1B or KIP1) is caused by increased
ubiquitin-mediated proteasomal degradation in
colorectal cancer, and has been associated with poor prognosis. CpG island methylator phenotype (CIMP) is a phenotype of
colorectal cancer with extensive promoter methylation, and associated with high degree of
microsatellite instability (MSI-H) and BRAF mutations. We have recently shown that both CIMP and MSI-H are inversely associated with downregulation of p21 (CDKN1A or CIP1), another
cyclin-dependent kinase inhibitor. However, no study to date has examined relationship between p27 and CIMP status in
colorectal cancer. Using MethyLight assays, we measured DNA methylation in five CIMP-specific gene promoters {CACNA1G, CDKN2A (p16), CRABP1, MLH1 and NEUROG1} in 706
colorectal cancer samples obtained from two large prospective cohorts. Among the 706
tumors, 112 (16%) were CIMP-high
tumors with >or=4/5 methylated promoters. We assessed p27 and p53 expressions by immunohistochemistry. Loss of nuclear p27 expression {observed in 231
tumors (33%)} was significantly associated with CIMP-high, MSI-H and BRAF mutations, and these associations were much more pronounced among p53-negative
tumors than p53-positive
tumors. When CIMP-high and non-CIMP-high
tumors were stratified by MSI status (or KRAS and BRAF status), CIMP-high and MSI-H (but not BRAF mutations) were still significantly associated with nuclear p27 loss. Nuclear p27 loss did not appear to be directly related to CDKN2A (p16) methylation. We conclude that downregulation of nuclear p27 is associated with CIMP-high and MSI-H in
colorectal cancer. These associations are stronger among p53 wild-type
tumors, implying important interplay of p27 and p53 functions (or dysfunctions) in the development of various molecular subtypes of
colorectal cancer.