IGFBP3 promoter methylation in colorectal cancer: relationship with microsatellite instability, CpG island methylator phenotype, and p53

Abstract

Insulin-like growth factor binding protein 3 (IGFBP3), which is induced by wild-type p53, regulates IGF and interacts with the TGF-beta pathway. IGFBP3 promoter methylation may occur in colorectal cancer with or without the CpG island methylator phenotype (CIMP), which is associated with microsatellite instability (MSI) and TGFBR2 mutation. We examined the relationship between IGFBP3 methylation, p53 expression, CIMP and MSI in 902 population-based colorectal cancers. Utilizing real-time PCR (MethyLight), we quantified promoter methylation in IGFBP3 and eight other CIMP-high-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1). IGFBP3 methylation was far more frequent in non-MSI-high CIMP-high tumors (85% = 35/41) than in MSI-high CIMP-high (49% = 44/90, P < .0001), MSI-high non-CIMP-high (17% = 6/36, P < .0001), and non-MSI-high non-CIMP-high tumors (22% = 152/680, P < .0001). Among CIMP-high tumors, the inverse relationship between MSI and IGFBP3 methylation persisted in p53-negative tumors (P < .0001), but not in p53-positive tumors. IGFBP3 methylation was associated inversely with TGFBR2 mutation in MSI-high non-CIMP-high tumors (P = .02). In conclusion, IGFBP3 methylation is inversely associated with MSI in CIMP-high colorectal cancers, and this relationship is limited to p53-negative tumors. Our data suggest complex relationship between global genomic/epigenomic phenomena (such as MSI/CIMP), single molecular events (e.g., IGFBP3 methylation, TP53 mutation, and TGFBR2 mutation), and the related pathways.

Keywords: CIMP; Colon cancer; IGFBP3; MSI; methylation.

Figure 1

Frequency of IGFBP3 methylation in four MSI/CIMP subtypes of colorectal cancer. CIMP, CpG island methylator phenotype; MSI, microsatellite instability; MSS, microsatellite stable.

Figure 2

The p53 pathway and IGFBP3.

Figure 3

Frequency of IGFBP3 methylation in CIMP-high tumors according to p53 and MSI status. Note that the inverse relationship between MSI and IGFBP3 methylation is present in p53-negative tumors, but not in p53-positive tumors. CIMP, CpG island methylator phenotype; MSI, microsatellite instability; MSS, microsatellite stable; NS, not significant.

Figure 4

Frequency of IGFBP3 methylation in CIMP-high tumors according to p21 and MSI status. Note that the inverse relationship between MSI and IGFBP3 methylation is present regardless of p21 status. CIMP, CpG island methylator phenotype; MSI, microsatellite instability; MSS, microsatellite stable.