Four Molecular Subtypes of Colorectal Cancer and Their Precursor Lesions

2011 ◽  
Vol 135 (6) ◽  
pp. 698-703
Author(s):  
Gyeong Hoon Kang
Keyword(s):  
Molecular Subtypes ◽  
Cpg Island ◽  
Colorectal Carcinogenesis ◽  
Colorectal Cancers ◽  
Precursor Lesions ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Epigenetic Instability ◽  
Geographic Differences ◽  
Methylator Phenotype

Abstract Context.—In addition to chromosomal instability and microsatellite instability (MSI), a third pathway, epigenetic instability, has been implicated in progression to colorectal carcinogenesis. CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that occur through the epigenetic instability pathway and that are characterized by widespread hypermethylation of promoter CpG island loci, resulting in the inactivation of several tumor suppressor genes or tumor-related genes. Colorectal cancers can be classified into 4 molecular subtypes according to their CIMP and MSI statuses: CIMP+/MSI+, CIMP+/MSI−, CIMP−/MSI+, and CIMP−/MSI−. There are differences between Western (United States and European Union) and Eastern (Korea and China) populations in the number of CRCs that are MSI+, and in the number of MSI+ CRCs that are CIMP+. Objective.—To review the clinicopathologic and molecular features of the 4 molecular subtypes of CRCs and their precursor lesions, and to emphasize geographic differences in CRCs between Eastern and Western populations. Data Sources.—This article is based on the author's own experimental data and a literature review of relevant articles indexed in PubMed (US National Library of Medicine). Conclusion.—The 4 molecular subtypes of CRC that are defined by their CIMP and MSI statuses are characterized by their own distinct clinicopathologic and molecular features and precursor lesions. In particular, the clinicopathologic features of MSI+ CRCs differ depending on the CIMP status. Further understanding of the heterogeneity in CRC molecular pathways may help to explain the diverse morphologic features of CRCs.

scholarly journals Molecular Subtypes of Colorectal Cancer and Their Clinicopathologic Features, With an Emphasis on the Serrated Neoplasia Pathway

2016 ◽  
Vol 140 (5) ◽  
pp. 406-412 ◽  
Author(s):  
Jeong Mo Bae ◽  
Jung Ho Kim ◽  
Gyeong Hoon Kang
Keyword(s):  
Colorectal Cancer ◽  
Complex Disease ◽  
Molecular Subtypes ◽  
Cpg Island ◽  
Colorectal Cancers ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Methylator Phenotype ◽  
Serrated Neoplasia Pathway ◽  
Molecular Carcinogenesis

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.

scholarly journals CpG Island Methylator Phenotype—A Hope for the Future or a Road to Nowhere?

2022 ◽  
Vol 23 (2) ◽  
pp. 830
Author(s):  
Karpiński Paweł ◽  
Sąsiadek Maria Małgorzata
Keyword(s):  
Diagnostic Marker ◽  
Cpg Island ◽  
Cpg Islands ◽  
Solid Tumours ◽  
Future Application ◽  
Colorectal Cancers ◽  
Cpg Island Methylator Phenotype ◽  
Pathological Characteristics ◽  
Epigenetic Instability ◽  
Methylator Phenotype

The CpG island methylator phenotype (CIMP) can be regarded as the most notable emanation of epigenetic instability in cancer. Since its discovery in the late 1990s, CIMP has been extensively studied, mainly in colorectal cancers (CRC) and gliomas. Consequently, knowledge on molecular and pathological characteristics of CIMP in CRC and other tumour types has rapidly expanded. Concordant and widespread hypermethylation of multiple CpG islands observed in CIMP in multiple cancers raised hopes for future epigenetically based diagnostics and treatments of solid tumours. However, studies on CIMP in solid tumours were hampered by a lack of generalisability and reproducibility of epigenetic markers. Moreover, CIMP was not a satisfactory marker in predicting clinical outcomes. The idea of targeting epigenetic abnormalities such as CIMP for cancer therapy has not been implemented for solid tumours, either. Twenty-one years after its discovery, we aim to cover both the fundamental and new aspects of CIMP and its future application as a diagnostic marker and target in anticancer therapies.

scholarly journals How theBRAFV600E Mutation Defines a Distinct Subgroup of Colorectal Cancer: Molecular and Clinical Implications

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Catherine E. Bond ◽  
Vicki L. J. Whitehall
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Early Event ◽  
Sporadic Colorectal Cancer ◽  
Cpg Island Methylator Phenotype ◽  
Distinct Subgroup ◽  
Molecular Features ◽  
Map Kinase Pathway ◽  
Methylator Phenotype ◽  
Kinase Pathway

TheBRAFoncogene is an integral component of the MAP kinase pathway, and an activating V600E mutation occurs in 15% of sporadic colorectal cancer. This is an early event in serrated pathway tumourigenesis, and theBRAFV600E has been commonly associated with the CpG island methylator phenotype, microsatellite instability (MSI), and a consistent clinical presentation including a proximal location and predilection for elderly females. A proportion of theBRAFmutant lesions remain as microsatellite stable (MSS), and in contrast to the MSI cancers, they have an aggressive phenotype and correlate with poor patient outcomes. Recent studies have found that they have clinical and molecular features of both theBRAFmutant/MSI and the conventionalBRAFwild-type cancers and comprise a distinct colorectal cancer subgroup. This review highlights the importance of theBRAFmutation occurring in colorectal cancer stratified for molecular background and discusses its prognostic and clinical significance.

scholarly journals Ethnicity and Risk for Colorectal Cancers Showing Somatic BRAF V600E Mutation or CpG Island Methylator Phenotype

2008 ◽  
Vol 17 (7) ◽  
pp. 1774-1780 ◽  
Author(s):  
Dallas R. English ◽  
Joanne P. Young ◽  
Julie A. Simpson ◽  
Mark A. Jenkins ◽  
Melissa C. Southey ◽  
...  
Keyword(s):  
Cpg Island ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Colorectal Cancers ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype

scholarly journals 745 Colorectal Cancers (CRCs) With the CpG Island Methylator Phenotype (CIMP) Do Not Show Improved Survival With 5-Fluorouracil (5FU)-Based Adjuvant Chemotherapy

2010 ◽  
Vol 138 (5) ◽  
pp. S-102
Author(s):  
Rodrigo Jover ◽  
Thuy-Phuong T. Nguyen ◽  
Lucía Pérez-Carbonell ◽  
Artemio Payá ◽  
Cristina Alenda ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Cpg Island ◽  
Colorectal Cancers ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype

CpG Island Methylator Phenotype in Colorectal Cancers: Comparison of the New and Classic CpG Island Methylator Phenotype Marker Panels

2008 ◽  
Vol 132 (10) ◽  
pp. 1657-1665 ◽  
Author(s):  
Sun Lee ◽  
Nam-Yun Cho ◽  
Eun Joo Yoo ◽  
Jung Ho Kim ◽  
Gyeong Hoon Kang
Keyword(s):  
Clinical Outcome ◽  
Microsatellite Instability ◽  
Braf Mutation ◽  
Cpg Island ◽  
Tumor Location ◽  
Colorectal Cancers ◽  
Clinicopathologic Features ◽  
Cpg Island Methylator Phenotype ◽  
P Values ◽  
Methylator Phenotype

Abstract Context.—CpG island methylator phenotype (CIMP) designates a subset of colorectal cancers featuring concordant hypermethylation of multiple promoter CpG islands. Little is known about the clinical outcome or histologic characteristics of CIMP-positive colorectal cancers defined by recently identified CpG island methylator phenotype panels. Objective.—To investigate and compare the molecular and clinicopathologic features of CIMP-positive colorectal cancers defined by classic (p16, hMLH1, MINT1, MINT2, MINT31) and new (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1) CIMP panels. Design.—We analyzed 130 colorectal cancers for hypermethylation of both panels using methylation-specific polymerase chain reaction. Results.—With at least 2 markers methylated, both classic (39/130; 23.1%) and new (23.1%) CIMP-positive colorectal cancers were significantly associated with proximal tumor location, microsatellite instability, and BRAF mutation (all P values were less than .05). The new panel outperformed the classic panel in detecting these features. With at least 3 markers methylated, new CIMP-positive colorectal cancers (16.9%) were closely associated with proximal tumor location, low frequency of KRAS mutation, and high frequency of BRAF mutation (all P values were less than .05), whereas classic CIMP-positive colorectal cancers (18.5%) were closely associated with proximal tumor location, frequent microsatellite instability, and frequent BRAF mutation (all P values were less than .05). Analyzing a combination of CIMP and microsatellite instability status, CIMP-positive/microsatellite instability–negative colorectal cancers had the worst clinical outcomes. Conclusions.—Whereas the classic panel outperformed in predicting clinical outcome, the new panel was superior in detecting known clinicopathologic features of CIMP but inferior in prognostication power.

Sign in / Sign up

Export Citation Format

Share Document