Abstract
Background: The current proposed model of colorectal tumorigenesis is based primarily on CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and methylation status of 0-6-Methylguanine DNA Methyltransferase (MGMT) and classifies tumors into five subgroups. The aim of this study is to validate this molecular classification and test its prognostic relevance. Methods: Three hundred two patients were included in this study. Molecular analysis was performed for five CIMP-related promoters (CRABP1, MLH1, p16INK4a, CACNA1G, NEUROG1), MGMT, MSI, KRAS, and BRAF. Methylation in at least 4 promoters or in one to three promoters was considered CIMP-high and CIMP-low (CIMP-H/L), respectively. Results: CIMP-H, CIMP-L, and CIMP-negative were found in 7.1, 43, and 49.9% cases, respectively. One hundred twenty-three tumors (41%) could not be classified into any one of the proposed molecular subgroups, including 107 CIMP-L, 14 CIMP-H, and two CIMP-negative cases. The 10 year survival rate for CIMP-high patients [22.6% (95%CI: 7–43)] was significantly lower than for CIMP-L or CIMP-negative (p = 0.0295). Only the combined analysis of BRAF and CIMP (negative versus L/H) led to distinct prognostic subgroups. Conclusion: Although CIMP status has an effect on outcome, our results underline the need for standardized definitions of low- and high-level CIMP, which clearly hinders an effective prognostic and molecular classification of colorectal cancer.
Highlights
Jass (2007) proposed a molecular classification of colorectal cancer based predominantly on five features: CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and methylation status of 0-6-Methylguanine DNA Methyltransferase (MGMT )
CIMP status has an effect on outcome, our results underline the need for standardized definitions of low- and highlevel CIMP, which clearly hinders an effective prognostic and molecular classification of colorectal cancer
CIMP-low (CIMPL), KRAS mutated, MGMT methylated, microsatellite stable (MSS)/ MSI-low (MSI-L) cancers were predicted in 20% of cases, while CIMP-H, BRAF mutated, MSI-H tumors in 12%, CIMP-H, BRAF mutated, chromosomally stable, MSS/MSI-L in 8%, and the hereditary Lynch syndrome CIMP-negative, BRAF mutation-negative, chromosomally stable, and MSI-H cancers found in 3% of all cases
Summary
Jass (2007) proposed a molecular classification of colorectal cancer based predominantly on five features: CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and methylation status of 0-6-Methylguanine DNA Methyltransferase (MGMT ). CIMP-low (CIMPL), KRAS mutated, MGMT methylated, MSS/ MSI-low (MSI-L) cancers were predicted in 20% of cases, while CIMP-H, BRAF mutated, MSI-H tumors in 12%, CIMP-H, BRAF mutated, chromosomally stable, MSS/MSI-L in 8%, and the hereditary Lynch syndrome CIMP-negative, BRAF mutation-negative, chromosomally stable, and MSI-H cancers found in 3% of all cases These new subgroupings form the basis of the current model of colorectal tumorigenesis. The current proposed model of colorectal tumorigenesis is based primarily on CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and methylation status of 0-6-Methylguanine DNA Methyltransferase (MGMT ) and classifies tumors into five subgroups. Conclusion: CIMP status has an effect on outcome, our results underline the need for standardized definitions of low- and highlevel CIMP, which clearly hinders an effective prognostic and molecular classification of colorectal cancer
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