Tumors with unmethylated MLH1 and the CpG island methylator phenotype are associated with a poor prognosis in stage II colorectal cancer patients

Abstract

We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP−/MLH1-U, or CIMP−/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production. Kaplan-Meier analyses revealed differences in both disease-free survival (DFS) and overall survival (OS) among the four groups. In a multivariate analysis, CIMP/MLH1 methylation status was predictive of both DFS and OS, and DFS and OS were shortest in CIMP+/MLH1-U stage II CRC patients. These results suggest that tumor subtype classification based on the combination of CIMP and MLH1 methylation status is informative in stage II CRC patients, and that CIMP+/MLH1-U tumors exhibit aggressive features and are associated with poor clinical outcomes.

Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis

“…In contrast, the likelihood of CIMP in Hispanic patients was indistinguishable from non-Hispanic white patients (OR = 1.04, 95% CI = 0.70-1.55). The association of CIMP-H with gender was studied across 56 studies, representing a total of 22,950 CRC patients [9] , [16] , [17] , [19] , [20] , [21] , [22] , [24] , [25] , [27] , [28] , [30] , [31] , [33] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] . The pooled prevalence of CIMP-H in males and females was 18% (95% CI = 15%-20%) and 26% (95% CI = 22%-29%), respectively, indicating a predisposition for CIMP-H tumors towards female gender (pooled OR = 1.59, 95% CI = 1.40-1.81) .…”

“…We studied the association of CIMP with tumor location, T staging, N staging, M staging, overall stage, well as synchronous CRC and presence of liver metastases. The association of CIMP with tumor location (right colon vs left colon + rectum) was investigated in 56 studies, representing a total of 20,782 CRC patients [16] , [17] , [19] , [23] , [24] , [25] , [28] , [29] , [30] , [31] , [33] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [47] , [48] , [50] , [51] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [72] , [73] , [74] , [76] , [77] , [78] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] . The pooled OR for right-sided location (as opposed to left-sided or rectal location) in the CIMP-H subgroup compared with the CIMP-0 subgroup was 4.84 (95% CI = 3.60-5.61, I 2 = 80%).…”

“…We studied the association of CIMP with key pathological characteristics in CRC tumors including lymphovascular invasion (LVI), tumor-infiltrating lymphocytes (TILS), peritumoral lymphocytes (PLS), vascular invasion, perineural invasion (PNI), presence of Crohn-like infiltrates, mucinous histology, and signet ring cell histologic characteristics. We investigated the association of CIMP with LVI in nine studies, representing 1572 CRC cases, and identified CIMP-H tumors to be associated with LVI as compared to CIMP-0 tumors (OR = 1.69, 95% CI = 1.23-2.31, I 2 = 18.1%) [30] , [38] , [43] , [45] , [50] , [59] , [62] , [65] , [72] . The association of CIMP with TILS was investigated in five studies, representing 2015 CRC cases [19] , [38] , [69] , [100] , [101] .…”

Knockdown of Tubulin Polymerization Promoting Protein Family Member 3 inhibits cell proliferation and invasion in human colorectal cancer

“…Despite significant improvement in curative surgical resection and adjuvant chemotherapeutic regimens, the majority of patients are often diagnosed at an advanced stage thus with poor prognosis 4 - 6 . A growing number of studies have demonstrated that complicated pathogenesis of CRC was a multi-step process involving in the deregulation of multiple oncogenes and tumor suppressors 7 - 10 , thereby emphasizing the need to further understand the molecular mechanisms underlying the formation and development of CRC.…”

Epigenetic Drug Therapy in the Treatment of Colorectal Cancer

“…It has been considered that dysfunction of DNA mismatch repair system is the main cause of MSI in CRC. Aberrant methylation or mutations of mismatch repair genes such as MLH1 is seen in MSI cancers [13]. CpG island methylator phenotype (CIMP) is the third cause of CRC pathogenesis, which demonstrates a global hypomethylation and also hypermethylation of CpG islands [14].…”