Epidemiology and Molecular-Pathologic Characteristics of CpG Island Methylator Phenotype (CIMP) in Colorectal Cancer.
CIMP
Colorectal
Epigenetics
Molecular
Pathology
Journal
Clinical colorectal cancer
ISSN: 1938-0674
Titre abrégé: Clin Colorectal Cancer
Pays: United States
ID NLM: 101120693
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
06
07
2020
revised:
15
09
2020
accepted:
18
09
2020
pubmed:
25
11
2020
medline:
15
12
2021
entrez:
24
11
2020
Statut:
ppublish
Résumé
CpG island methylator phenotype (CIMP) forms a distinct epigenetic phenotype in colorectal cancer (CRC). Though associated with distinct clinicopathologic characteristics, limited evidence exists of the association of CIMP with patient's reported lifestyle factors and tumor molecular characteristics. We assessed the associations of these characteristics in a pooled analysis of CRC patients. We pooled data from 3 CRC patient cohorts: Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC), biomarker-based protocol (Integromics), and The Cancer Genome Atlas (TCGA). CIMP was measured using the classical 6-gene methylated-in-tumor (MINT) marker panel (MINT1, MINT2, MINT31, p14, p16, and MLH1) in ATTACC and genome-wide human methylation arrays in Integromics and TCGA, respectively. CIMP-High (CIMP-H) was defined as ≥ 3 of 6 methylated markers in ATTACC. In TCGA and Integromics, CIMP-H group was defined on the basis of clusters of methylation profiles and high levels of methylation in tumor samples. Baseline comparisons of characteristics across CIMP groups (CIMP-H vs. CIMP-0) were performed by Student t test or chi-square test for continuous or categorical variables, respectively. Further logistic regression analyses were performed to compute the odds ratio (OR) of these associations. Pooled prevalence of CIMP-H was 22% across 3 data sets. CIMP-H CRC tumors were associated with older age at diagnosis (OR, 1.02; 95% confidence interval [CI], 1.01, 1.03), microsatellite instability-high (MSI-H) status (OR, 9.15; 95% CI, 4.45, 18.81), BRAF mutation (OR, 7.70; 95% CI, 4.98, 11.87), right-sided tumor location (OR, 2.40; 95% CI, 1.78, 3.22), poor differentiation (OR, 2.94; 95% CI, 1.95, 4.45), and mucinous histology (OR, 2.47; 95% CI, 1.77, 3.47), as reported previously in the literature. CIMP-H tumors were also found to be associated with self-reported history of alcohol consumption (OR, ever vs. never, 1.58; 95% CI, 1.07, 2.34). Pathologically, CIMP-H tumors were associated with the presence of intraepithelial lymphocytes (OR, 3.31; 95% CI, 1.41, 7.80) among patients in the Integromics cohort. CIMP-H tumors were associated with history of alcohol consumption and presence of intraepithelial lymphocytes. In addition, we confirmed the previously known association of CIMP with age, MSI-H status, BRAF mutation, sidedness, and mucinous histology. Molecular pathologic epidemiology associations help us explore the underlying association of lifestyle and clinical factors with molecular subsets like CIMP and help guide cancer prevention and treatment strategies.
Sections du résumé
BACKGROUND
CpG island methylator phenotype (CIMP) forms a distinct epigenetic phenotype in colorectal cancer (CRC). Though associated with distinct clinicopathologic characteristics, limited evidence exists of the association of CIMP with patient's reported lifestyle factors and tumor molecular characteristics. We assessed the associations of these characteristics in a pooled analysis of CRC patients.
PATIENTS AND METHODS
We pooled data from 3 CRC patient cohorts: Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC), biomarker-based protocol (Integromics), and The Cancer Genome Atlas (TCGA). CIMP was measured using the classical 6-gene methylated-in-tumor (MINT) marker panel (MINT1, MINT2, MINT31, p14, p16, and MLH1) in ATTACC and genome-wide human methylation arrays in Integromics and TCGA, respectively. CIMP-High (CIMP-H) was defined as ≥ 3 of 6 methylated markers in ATTACC. In TCGA and Integromics, CIMP-H group was defined on the basis of clusters of methylation profiles and high levels of methylation in tumor samples. Baseline comparisons of characteristics across CIMP groups (CIMP-H vs. CIMP-0) were performed by Student t test or chi-square test for continuous or categorical variables, respectively. Further logistic regression analyses were performed to compute the odds ratio (OR) of these associations.
RESULTS
Pooled prevalence of CIMP-H was 22% across 3 data sets. CIMP-H CRC tumors were associated with older age at diagnosis (OR, 1.02; 95% confidence interval [CI], 1.01, 1.03), microsatellite instability-high (MSI-H) status (OR, 9.15; 95% CI, 4.45, 18.81), BRAF mutation (OR, 7.70; 95% CI, 4.98, 11.87), right-sided tumor location (OR, 2.40; 95% CI, 1.78, 3.22), poor differentiation (OR, 2.94; 95% CI, 1.95, 4.45), and mucinous histology (OR, 2.47; 95% CI, 1.77, 3.47), as reported previously in the literature. CIMP-H tumors were also found to be associated with self-reported history of alcohol consumption (OR, ever vs. never, 1.58; 95% CI, 1.07, 2.34). Pathologically, CIMP-H tumors were associated with the presence of intraepithelial lymphocytes (OR, 3.31; 95% CI, 1.41, 7.80) among patients in the Integromics cohort.
CONCLUSION
CIMP-H tumors were associated with history of alcohol consumption and presence of intraepithelial lymphocytes. In addition, we confirmed the previously known association of CIMP with age, MSI-H status, BRAF mutation, sidedness, and mucinous histology. Molecular pathologic epidemiology associations help us explore the underlying association of lifestyle and clinical factors with molecular subsets like CIMP and help guide cancer prevention and treatment strategies.
Identifiants
pubmed: 33229221
pii: S1533-0028(20)30136-5
doi: 10.1016/j.clcc.2020.09.007
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
137-147.e1Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.