Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location

Abstract Background Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Methods We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. Results Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors. Conclusions We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

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The Role of the CpG Island Methylator Phenotype in Colorectal Cancer Prognosis Depends on Microsatellite Instability Screening Status

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-09-2594 ◽

2010 ◽

Vol 16 (6) ◽

pp. 1845-1855 ◽

Cited By ~ 126

Author(s):

Anna M. Dahlin ◽

Richard Palmqvist ◽

Maria L. Henriksson ◽

Maria Jacobsson ◽

Vincy Eklöf ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Cpg Island ◽

Cancer Prognosis ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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Clinicopathological and Molecular Profiles of Sporadic Microsatellite Unstable Colorectal Cancer with or without the CpG Island Methylator Phenotype (CIMP)

Cancers ◽

10.3390/cancers12113487 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3487

Author(s):

Shih-Ching Chang ◽

Anna Fen-Yau Li ◽

Pei-Ching Lin ◽

Chun-Chi Lin ◽

Hung-Hsin Lin ◽

...

Keyword(s):

Colorectal Cancer ◽

Cpg Island ◽

Gene Mutations ◽

Proximal Colon ◽

Tnm Stage ◽

Cpg Island Methylator Phenotype ◽

Kras Mutations ◽

Methylator Phenotype ◽

Next Generation Sequencing Ngs ◽

Mutation Spectra

Background: The 5’-C-phosphate-G-3’ island methylator phenotype (CIMP) is a specific phenotype of colorectal cancer (CRC) associated with microsatellite instability-high (MSI-high) tumors. Methods: In this study, we determined the CIMP status using eight methylation markers in 92 MSI-high CRC patients after excluding five germline mismatch repair (MMR) gene mutations analyzed by next-generation sequencing (NGS) and confirmed by Sanger sequencing. The mutation spectra of 22 common CRC-associated genes were analyzed by NGS. Results: Of the 92 sporadic MSI-high tumors, 23 (25%) were considered CIMP-high (expressed more than 5 of 8 markers). CIMP-high tumors showed proximal colon preponderance and female predominance. The mutation profiles of CIMP-high tumors were significantly different from those of CIMP-low or CIMP-0 tumors (i.e., higher frequencies of BRAF, POLD1, MSH3, and SMAD4 mutations but lower frequencies of APC, TP53, and KRAS mutations). Multivariate analysis demonstrated that tumor, node, metastasis (TNM) stage was the independent prognostic factor affecting overall survival (OS). Among the MSI-high cases, the CIMP status did not impact the outcome of patients with MSI-high tumors. Conclusions: Only TNM stage was a statistically significant predictor of outcomes independent of CIMP profiles in MSI-high CRC patients. Sporadic MSI-high CRCs with different mechanisms of carcinogenesis have specific mutation profiles and clinicopathological features.

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TGFBR2 mutation is correlated with CpG island methylator phenotype in microsatellite instability-high colorectal cancer

Human Pathology ◽

10.1016/j.humpath.2006.10.005 ◽

2007 ◽

Vol 38 (4) ◽

pp. 614-620 ◽

Cited By ~ 31

Author(s):

Shuji Ogino ◽

Takako Kawasaki ◽

Akiyo Ogawa ◽

Gregory J. Kirkner ◽

Massimo Loda ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Cpg Island ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer

International Journal of Cancer ◽

10.1002/ijc.21701 ◽

2006 ◽

Vol 118 (11) ◽

pp. 2765-2771 ◽

Cited By ~ 86

Author(s):

Hirofumi Tanaka ◽

Guoren Deng ◽

Koji Matsuzaki ◽

Sanjay Kakar ◽

Grace E. Kim ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Braf Mutation ◽

Cpg Island ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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The Methylation of SDC2 and TFPI2 Defined Three Methylator Phenotypes of Colorectal Cancer

10.21203/rs.3.rs-1022929/v1 ◽

2021 ◽

Author(s):

Ruixue Lei ◽

Yanteng Zhao ◽

Kai Huang ◽

Qian Wang ◽

Kangkang Wan ◽

...

Keyword(s):

Colorectal Cancer ◽

Cpg Island ◽

Methylation Status ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Tumor Location ◽

Functional Enrichment ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype ◽

Almost All

Abstract BackgroudMethylated SDC2 and TFPI2 are applied frequently for the early detection of colorectal cancer (CRC). However, they often miss some positive samples, which directly affects their sensitivities, and the underlining mechanism is not well known.Methods:CRC samples from TCGA and GEO datasets were divided into three groups, Highmethylation/ High-methylation (HH), High-methylation/Low-methylation (HL), and Lowmethylation/Low-methylation (LL) according to the methylation status of SDC2 and TFPI2 promoters. Variations in age, tumor location, and microsatellite instable were then assessed between the three groups and verified in our custom cohort.ResultsSamples of HL group preferred to derive from left-sided CRCs (P < 0.05). HH samples showed the highest microsatellite instability and mutation load (mean nonsynonymous mutations for HH/HL/LL: 10.55/3.91/7.02, P = 0.0055). Almost all mutations of BRAF, one of the five typical CpG island methylator phenotype (CIMP) related genes, were observed in HH group (HH/HL/LL: 51/0/1, P = 0.018). Besides, older patients were frequently found in HH group. Expression analysis identified 37, 84, and 22 group-specific differentially expressed genes (DEGs) for HH, HL, and LL, respectively. Functional enrichment analysis revealed that HH-specific DEGs were mainly related to transcription regulation, while LL-specific DEGs were enriched in the biological processes of extracellular matrix interaction and cell migration.Conclusions:The three methylation phenotypes identified based on SDC2 and TFPI2 methylation status showed extensive variations in tumor location, patient age, MSI and ECM biology processes, suggesting that these respective sides should be considered when developing new methylation-based biomarkers for CRC detection.

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

Archives of Pathology & Laboratory Medicine ◽

10.5858/2008-132-1657-cimpic ◽

2008 ◽

Vol 132 (10) ◽

pp. 1657-1665 ◽

Cited By ~ 1

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.

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