Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Abstract

MSH3 gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as “elevated microsatellite alterations at selected tetranucleotide repeats” (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for MSH3, MCC, CDKN2A (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with ≥3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H.

Epigenetic Approach on Colorectal Cancer Systemic Therapy: Promising yet a Long Way to Go

“…Several CIMP markers have been identified, e.g. CKDN2A, MINT1, MINT2, MINT3, and MLH1 (17,18). Different epigenotype classifications were suggested.…”

“…Different epigenotype classifications were suggested. According to the proportion of methylated marker loci, CRC was grouped into three different epigenotypes: high CIMP, low CIMP, and negative CIMP (18). Another study divides CRC into five molecular subtypes depending on CIN and CIMP status.…”

MCC Gene Silencing Is a CpG Island Methylator Phenotype-Associated Factor That Predisposes Colon Cancer Cells to Irinotecan and Olaparib

“…MCC is emerging as a tumor suppressor involved in at least two cellular processes, the DNA damage response and cell–cell adhesion [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. We showed that CpG island hypermethylation is a common cause of MCC silencing in serrated polyps and carcinomas in the colon [ 5 , 11 ]. MCC -methylated tumors are associated with poorly differentiated, circumferential, and mucinous tumors, as well as increasing T stage, larger tumor size, proximal colon location [ 2 ], and down-regulation of MSH3 gene expression [ 11 ].…”

“…We showed that CpG island hypermethylation is a common cause of MCC silencing in serrated polyps and carcinomas in the colon [ 5 , 11 ]. MCC -methylated tumors are associated with poorly differentiated, circumferential, and mucinous tumors, as well as increasing T stage, larger tumor size, proximal colon location [ 2 ], and down-regulation of MSH3 gene expression [ 11 ]. MCC -methylated cancers include CpG island methylator phenotype (CIMP)-positive tumors [ 5 , 11 ] that are potentially more responsive to irinotecan [ 12 ].…”

“…MCC -methylated tumors are associated with poorly differentiated, circumferential, and mucinous tumors, as well as increasing T stage, larger tumor size, proximal colon location [ 2 ], and down-regulation of MSH3 gene expression [ 11 ]. MCC -methylated cancers include CpG island methylator phenotype (CIMP)-positive tumors [ 5 , 11 ] that are potentially more responsive to irinotecan [ 12 ]. These findings have raised the prospect of exploiting MCC silencing in cancer therapy, and particularly in relation to irinotecan responsiveness [ 3 ].…”