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

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.

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Association between risk factors, molecular features and CpG island methylator phenotype colorectal cancer among different age groups in a Taiwanese cohort

British Journal of Cancer ◽

10.1038/s41416-021-01300-5 ◽

2021 ◽

Author(s):

Kuo-Hsing Chen ◽

Liang-In Lin ◽

Chang-Tsu Yuan ◽

Li-Hui Tseng ◽

Yu-Liang Chao ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Factors ◽

Cpg Island ◽

Age Groups ◽

Cpg Island Methylator Phenotype ◽

Molecular Features ◽

Methylator Phenotype

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Erratum to “Prognostic and Predictive Value of CpG Island Methylator Phenotype in Patients with Locally Advanced Nonmetastatic Sporadic Colorectal Cancer”

Gastroenterology Research and Practice ◽

10.1155/2014/418148 ◽

2014 ◽

Vol 2014 ◽

pp. 1-1

Author(s):

Yuwei Wang ◽

Yadong Long ◽

Ye Xu ◽

Zuqing Guan ◽

Peng Lian ◽

...

Keyword(s):

Colorectal Cancer ◽

Predictive Value ◽

Cpg Island ◽

Locally Advanced ◽

Sporadic Colorectal Cancer ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2015-0310-ra ◽

2016 ◽

Vol 140 (5) ◽

pp. 406-412 ◽

Cited By ~ 40

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.

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Polymorphisms in methyl-group metabolism genes and risk of sporadic colorectal cancer with relation to the CpG island methylator phenotype

Cancer Epidemiology ◽

10.1016/j.canep.2010.03.002 ◽

2010 ◽

Vol 34 (3) ◽

pp. 338-344 ◽

Cited By ~ 24

Author(s):

Pawel Karpinski ◽

Aleksander Myszka ◽

David Ramsey ◽

Blazej Misiak ◽

Justyna Gil ◽

...

Keyword(s):

Colorectal Cancer ◽

Cpg Island ◽

Sporadic Colorectal Cancer ◽

Cpg Island Methylator Phenotype ◽

Methyl Group ◽

Methylator Phenotype

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Unique characteristics of CpG island methylator phenotype (CIMP) in a Chinese population with colorectal cancer

BMC Gastroenterology ◽

10.1186/s12876-019-1086-x ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Jiang Liu ◽

Li Tang ◽

Jinhua Yi ◽

Guimei Li ◽

Youwang Lu ◽

...

Keyword(s):

Colorectal Cancer ◽

Chinese Population ◽

Cpg Island ◽

Molecular Characteristics ◽

Cpg Island Methylator Phenotype ◽

Chinese Populations ◽

Molecular Features ◽

Tumour Location ◽

Low Incidence ◽

Methylator Phenotype

Abstract Background Molecular characteristics of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been well documented in Western, but not in Chinese, populations. Methods We investigated the incidence of CIMP, BRAF/KRAS mutation, and microsatellite instability (MSI) in a Chinese population with CRC (n = 401) and analysed associations between CIMP status and clinicopathological and molecular features. Results A total of 41 cases, 310 cases, and 40 cases were classified as CIMP-high, CIMP-low, and CIMP-negative, respectively. We detected a significantly low incidence of BRAF mutation in adenomas (2%) and CRC (0.7%), and a relatively low incidence of KRAS mutation (24.9%) compared with that in other populations. We also detected a relatively low incidence of CIMP-high (10.2%), which was significantly associated with younger age (≤49 years of age), female sex, and proximal tumour location. Conclusions This study revealed unique characteristics of CIMP in a Chinese population with colorectal cancer. Developing specific CIMP markers based on unique populations or ethnic groups will further help to fully elucidate CIMP pathogenesis.

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CpG Island Methylator Phenotype and Prognosis of Colorectal Cancer in Northeast China

BioMed Research International ◽

10.1155/2014/236361 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 10

Author(s):

Xia Li ◽

Fulan Hu ◽

Yibaina Wang ◽

Xiaoping Yao ◽

Zuoming Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Promoter Methylation ◽

Northeast China ◽

Proportional Hazards ◽

Cpg Island ◽

Sporadic Colorectal Cancer ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype ◽

Worse Prognosis

Purpose. To investigate the association between CpG island methylator phenotype (CIMP) and the overall survival of sporadic colorectal cancer (CRC) in Northeast China.Methods. 282 sporadic CRC patients were recruited in this study. We selectedMLH1,MGMT,p16,APC,MINT1,MINT31, andRUNX3as the CIMP panel markers. The promoter methylation was assessed by methylation sensitive high resolution melting (MS-HRM). Proportional hazards-regression models were fitted with computing hazard ratios (HR) and the corresponding 95% confidence intervals (95% CI).Results. 12.77% (36/282) of patients were CIMP-0, 74.1% (209/282) of patients were CIMP-L, and 13.12% (37/282) of patients were CIMP-H. The five-year survival of the 282 CRC patients was 58%. There was significant association betweenAPCgene promoter methylation and CRC overall survival (HR = 1.61; 95% CI: 1.05–2.46;P=0.03). CIMP-H was significantly associated with worse prognosis compared to CIMP-0 (HR = 3.06; 95% CI: 1.19–7.89;P=0.02) and CIMP-L (HR = 1.97; 95% CI: 1.11–3.48;P=0.02), respectively. While comparing with the combine of CIMP-L and CIMP-0 (CIMP-L/0), CIMP-H also presented a worse prognosis (HR = 2.31; 95% CI: 1.02–5.24;P=0.04).Conclusion. CIMP-H may be a predictor of a poor prognosis of CRC in Northeast China patients.

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Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability

Tumor Biology ◽

10.1177/1010428320938492 ◽

2020 ◽

Vol 42 (7) ◽

pp. 101042832093849 ◽

Cited By ~ 1

Author(s):

Ana María Wielandt ◽

Claudia Hurtado ◽

Mauricio Moreno C ◽

Cynthia Villarroel ◽

Magdalena Castro ◽

...

Keyword(s):

Colorectal Cancer ◽

Latin American ◽

Chromosomal Instability ◽

Cpg Island ◽

Sporadic Colorectal Cancer ◽

Cpg Island Methylator Phenotype ◽

Kras Mutations ◽

Group 3 ◽

Methylator Phenotype ◽

Chilean Population

Molecular classification of colorectal cancer is difficult to implement in clinical settings where hundreds of genes are involved, and resources are limited. This study aims to characterize the molecular subtypes of patients with sporadic colorectal cancer based on the three main carcinogenic pathways microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) in a Chilean population. Although several reports have characterized colorectal cancer, most do not represent Latin-American populations. Our study includes 103 colorectal cancer patients who underwent surgery, without neoadjuvant treatment, in a private hospital between 2008 and 2017. MSI, CIN, and CIMP status were assessed. Frequent mutations in KRAS, BRAF, and PIK3CA genes were analyzed by Sanger sequencing, and statistical analysis was performed by Fisher’s exact and/or chi-square test. Survival curves were estimated with Kaplan–Meier and log-rank test. Based on our observations, we can classify the tumors in four subgroups, Group 1: MSI-high tumors (15%) are located in the right colon, occur at older age, and 60% show a BRAF mutation; Group 2: CIN-high tumors (38%) are in the left colon, and 26% have KRAS mutations. Group 3: [MSI/CIN/CIMP]-low/negative tumors (30%) are left-sided, and 39% have KRAS mutations; Group 4: CIMP-high tumors (15%) were more frequent in men and left side colon, with 27% KRAS and 7% presented BRAF mutations. Three percent of patients could not be classified. We found that CIMP-high was associated with a worse prognosis, both in MSI-high and MSI stable patients (p = 0.0452). Group 3 (Low/negative tumors) tend to have better overall survival compared with MSI-high, CIMP-high, and CIN-high tumors. This study contributes to understanding the heterogeneity of tumors in the Chilean population being one of the few characterizations performed in Latin-America. Given the limited resources of these countries, these results allow to improve molecular characterization in Latin-American colorectal cancer populations and confirm the possibility of using the three main carcinogenic pathways to define therapeutic strategies.

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The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer

Gastroenterology ◽

10.1053/j.gastro.2006.09.018 ◽

2007 ◽

Vol 132 (1) ◽

pp. 127-138 ◽

Cited By ~ 198

Author(s):

Ajay Goel ◽

Takeshi Nagasaka ◽

Christian N. Arnold ◽

Toru Inoue ◽

Cody Hamilton ◽

...

Keyword(s):

Colorectal Cancer ◽

Chromosomal Instability ◽

Cpg Island ◽

Sporadic Colorectal Cancer ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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Prognostic and Predictive Value of CpG Island Methylator Phenotype in Patients with Locally Advanced Nonmetastatic Sporadic Colorectal Cancer

Gastroenterology Research and Practice ◽

10.1155/2014/436985 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Yuwei Wang ◽

Yadong Long ◽

Ye Xu ◽

Zuqing Guan ◽

Peng Lian ◽

...

Keyword(s):

Colorectal Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Cpg Island ◽

Locally Advanced ◽

Stage Ii ◽

Sporadic Colorectal Cancer ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype ◽

Colorectal Cancer Patients

Purpose. In the present study, the prognostic significance of CpG island methylator phenotype (CIMP) in stage II/III sporadic colorectal cancer was evaluated using a five-gene panel.Methods. Fifty stage II/III colorectal cancer patients who received radical resection were included in this study. Promoter methylation of p14ARF, hMLH1, p16INK4a, MGMT, and MINT1 was determined by methylation specific polymerase chain reaction (MSP). CIMP positive was defined as hypermethylation of three or more of the five genes. Impact factors on disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier method (log-rank test) and adjusted Cox proportional hazards model.Results. Twenty-four percent (12/50) of patients were characterized as CIMP positive. Univariate analysis showed stage III (P=0.049) and CIMP positive (P=0.014) patients who had significantly inferior DFS. In Cox regression analysis, CIMP positive epigenotype was independently related with poor DFS with HR = 2.935 and 95% CI: 1.193–7.220 (P=0.019). In patients with CIMP positive tumor, those receiving adjuvant chemotherapy had a poor DFS than those without adjuvant chemotherapy (P=0.023).Conclusions. CIMP positive was significantly correlated with decreased DFS in stage II/III colorectal cancer. Patients with CIMP positive locally advanced sporadic colorectal cancers may not benefit from 5-fluorouracil based adjuvant chemotherapy.

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