Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a Population-Based Series of 582 Cases

Abstract

The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a populationbased series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMPLow status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P < 0.001). KRAS mutations were more associated with CIMP-High and CIMPLow status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status [CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37-2.51; CIMP-High, HR, 2.90; 95% CI, 1.53-5.49 compared with No-CIMP]. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer. [Cancer Res 2008;68(20):8541-6]

Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features

“…[26][27][28] Along the adenoma-carcinoma sequence, colorectal tumorigenesis can progress through either chromosomal instability pathway with multiple alterations in chromosome number, chromosomal rearrangements, or gene amplications or the microsatellite instability pathway as a result of a germiline mutation in a DNA mismatch repair protein. 29 More recently, colorectal carcinomas that exhibit high levels of promoter methylation of CpG islands have been identified (CIMP-high, CIMP-H), 30,31 and these CIMP-H carcinomas are thought to arise through a precursor sessile serrated polyp/adenoma. 29 Abnormalities of the Wnt signaling pathway, particularly APC inactivation with nuclear localization of b-catenin, and activating KRAS mutations are common events in the adenoma-carcinoma sequence of the chromosomal instability pathway.…”

Oncogenic mutations as predictive factors in colorectal cancer

“…Despite its predictive role, KRAS mutation has not been shown as a prognostic marker in many large-scale studies (Finkelstein et al, 1993;Samowitz et al, 2000;Gnanasampanthan et al, 2001;Ince et al, 2005;Barault et al, 2008b;Zlobec et al, 2009;Ogino et al, 2009a;Ogino et al, 2009b;Roth et al, 2010), except for one large study (Barault et al, 2008a). Overall evidence supports a null prognostic role of KRAS mutation even if a previous meta-analyses (Andreyev et al, 1998;Andreyev et al, 2001) led to wrong conclusions likely due to the well-known positive publication bias.…”

Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

“…Along with others, we have reported a worse prognosis in colorectal cancer patients with CIMP-low or CIMP-high, compared with CIMPnegative tumors, particularly in combination with MSS. 4,[9][10][11][12] However, results from other large studies have not been entirely consistent, [13][14][15][16][17][18] and consensus has thus not been reached. One factor contributing to the discrepancy of results in the many studies is the lack of information regarding BRAF mutation, which has shown to be a major confounding factor in studies of CIMP status and colorectal cancer patient survival.…”