Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway

Context.—Colorectal cancer is a heterogeneous disease entity with 3 molecular carcinogenesis pathways and 2 morphologic multistep pathways. Right-sided colon cancers and left-sided colon and rectal cancers exhibit differences in their incidence rates according to geographic region, age, and sex. A linear tendency toward increasing frequencies of microsatellite instability–high or CpG island methylator phenotype–high cancers in subsites along the bowel from the rectum to the cecum or the ascending colon accounts for the differences in tumor phenotypes associated with these subsites. The molecular subtypes of colorectal cancers exhibit different responses to adjuvant therapy, which might be responsible for differences in subtype-specific survival. Objectives.—To review the clinicopathologic and molecular features of the molecular subtypes of colorectal cancer generated by combined CpG island methylator phenotype and microsatellite statuses, to integrate these features with the most recent findings in the context of the prognostic implications of molecular subtypes, and to emphasize the necessity of developing molecular markers that enable the identification of adenocarcinomas involving the serrated neoplasia pathway. Data Sources.—Based on the authors' own experimental data and a review of the pertinent literature. Conclusions.—Because colorectal cancers arise from 2 different morphologic multistep carcinogenesis pathways with varying contributions from 3 different molecular carcinogenesis pathways, colorectal cancer is a heterogeneous and complex disease. Thus, molecular subtyping of colorectal cancers is an important approach to characterizing their heterogeneity with respect to not only prognosis and therapeutic response but also biology and natural history.

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746 CpG Island Methylator Phenotype May Confer a Survival Benefit From Fluoropyrimidine-Based Adjuvant Chemotherapy on Patients With Stage II or III Colorectal Carcinomas

Gastroenterology ◽

10.1016/s0016-5085(10)60467-2 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-102

Author(s):

Young Kyung Sung ◽

Byung-Hoon Min ◽

Young-Ho Kim ◽

Dong Kyung Chang ◽

Hee Cheol Kim ◽

...

Keyword(s):

Adjuvant Chemotherapy ◽

Survival Benefit ◽

Cpg Island ◽

Stage Ii ◽

Colorectal Carcinomas ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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Chromosomally and microsatellite stable colorectal carcinomas without the CpG island methylator phenotype in a molecular classification

International Journal of Oncology ◽

10.3892/ijo_00000343 ◽

2009 ◽

Cited By ~ 3

Author(s):

Prall

Keyword(s):

Cpg Island ◽

Molecular Classification ◽

Colorectal Carcinomas ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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Single nucleotide polymorphism array analysis of microsatellite-stable, diploid/near-diploid colorectal carcinomas without the CpG island methylator phenotype

Oncology Letters ◽

10.3892/ol.2012.1006 ◽

2012 ◽

Vol 5 (1) ◽

pp. 173-178 ◽

Cited By ~ 6

Author(s):

MICHAEL LINNEBACHER ◽

CHRISTIANE OSTWALD ◽

DIRK KOCZAN ◽

TAREQ SALEM ◽

BJÖRN SCHNEIDER ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Cpg Island ◽

Single Nucleotide Polymorphism Array ◽

Colorectal Carcinomas ◽

Nucleotide Polymorphism ◽

Array Analysis ◽

Cpg Island Methylator Phenotype ◽

Single Nucleotide ◽

Methylator Phenotype

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

Cancers ◽

10.3390/cancers13143529 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3529

Author(s):

Sabine Meessen ◽

Nicola Currey ◽

Zeenat Jahan ◽

Hannah W. Parker ◽

Mark A. Jenkins ◽

...

Keyword(s):

Colorectal Cancer ◽

Cpg Island ◽

Predictive Marker ◽

Proximal Colon ◽

Marker Genes ◽

Colorectal Carcinomas ◽

Loss Of Function ◽

Cpg Island Methylator Phenotype ◽

Tetranucleotide Repeat ◽

Methylator Phenotype

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.

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