Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer

A Systematic Review and Meta-analysis

Shailesh M. Advani, Pragati Advani, Stacia M. DeSantis, Derek Brown, Helena M. VonVille, Michael Lam, Jonathan M. Loree, Amir Mehrvarz Sarshekeh, Jan Bressler, David Lopez, Carrie R. Daniel, Michael D. Swartz, Scott Kopetz

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.

Original languageEnglish (US)
Pages (from-to)1188-1201
Number of pages14
JournalTranslational Oncology
Volume11
Issue number5
DOIs
StatePublished - Oct 1 2018
Externally publishedYes

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CpG Islands
Meta-Analysis
Colorectal Neoplasms
Phenotype
Mutation
Neoplasms
Active Immunity
Fusobacterium nucleatum
Tumor-Infiltrating Lymphocytes
Microsatellite Instability
DNA Methylation
Tumor Suppressor Genes
Odds Ratio
Lymphocytes
Bacteria

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer : A Systematic Review and Meta-analysis. / Advani, Shailesh M.; Advani, Pragati; DeSantis, Stacia M.; Brown, Derek; VonVille, Helena M.; Lam, Michael; Loree, Jonathan M.; Sarshekeh, Amir Mehrvarz; Bressler, Jan; Lopez, David; Daniel, Carrie R.; Swartz, Michael D.; Kopetz, Scott.

In: Translational Oncology, Vol. 11, No. 5, 01.10.2018, p. 1188-1201.

Research output: Contribution to journalArticle

Advani, SM, Advani, P, DeSantis, SM, Brown, D, VonVille, HM, Lam, M, Loree, JM, Sarshekeh, AM, Bressler, J, Lopez, D, Daniel, CR, Swartz, MD & Kopetz, S 2018, 'Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis', Translational Oncology, vol. 11, no. 5, pp. 1188-1201. https://doi.org/10.1016/j.tranon.2018.07.008
Advani, Shailesh M. ; Advani, Pragati ; DeSantis, Stacia M. ; Brown, Derek ; VonVille, Helena M. ; Lam, Michael ; Loree, Jonathan M. ; Sarshekeh, Amir Mehrvarz ; Bressler, Jan ; Lopez, David ; Daniel, Carrie R. ; Swartz, Michael D. ; Kopetz, Scott. / Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer : A Systematic Review and Meta-analysis. In: Translational Oncology. 2018 ; Vol. 11, No. 5. pp. 1188-1201.
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abstract = "BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20{\%} of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.",
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T1 - Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer

T2 - A Systematic Review and Meta-analysis

AU - Advani, Shailesh M.

AU - Advani, Pragati

AU - DeSantis, Stacia M.

AU - Brown, Derek

AU - VonVille, Helena M.

AU - Lam, Michael

AU - Loree, Jonathan M.

AU - Sarshekeh, Amir Mehrvarz

AU - Bressler, Jan

AU - Lopez, David

AU - Daniel, Carrie R.

AU - Swartz, Michael D.

AU - Kopetz, Scott

PY - 2018/10/1

Y1 - 2018/10/1

N2 - BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.

AB - BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.

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