MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers

Kaori Shima, Teppei Morikawa, Yoshifumi Baba, Katsuhiko Nosho, Maiko Suzuki, Mai Yamauchi, Marika Hayashi, Edward Giovannucci, Charles S. Fuchs, Shuji Ogino

Research output: Contribution to journalArticle

Abstract

Objective: O 6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme. MGMT promoter hypermethylation and epigenetic silencing often occur as early events in carcinogenesis. However, prognostic significance of MGMT alterations in colorectal cancer remains uncertain. Methods: Utilizing a database of 855 colon and rectal cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected MGMT promoter hypermethylation in 325 tumors (38%) by MethyLight and loss of MGMT expression in 37% (247/672) of tumors by immunohistochemistry. We assessed the CpG island methylator phenotype (CIMP) using eight methylation markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and LINE-1 (L1) hypomethylation, TP53 (p53), and microsatellite instability (MSI). Results: MGMT hypermethylation was not associated with colorectal cancer-specific mortality in univariate or multivariate Cox regression analysis [adjusted hazard ratio (HR) = 1.03; 95% confidence interval (CI), 0.79-1.36] that adjusted for clinical and tumor features, including CIMP, MSI, and BRAF mutation. Similarly, MGMT loss was not associated with patient survival. MGMT loss was associated with G>A mutations in KRAS (p = 0.019) and PIK3CA (p = 0.0031). Conclusions: Despite a well-established role of MGMT aberrations in carcinogenesis, neither MGMT promoter methylation nor MGMT loss serves as a prognostic biomarker in colorectal cancer.

Original languageEnglish (US)
Pages (from-to)301-309
Number of pages9
JournalCancer Causes and Control
Volume22
Issue number2
DOIs
StatePublished - Feb 1 2011

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Methyltransferases
Methylation
Colorectal Neoplasms
DNA
Microsatellite Instability
CpG Islands
Carcinogenesis
O(6)-Methylguanine-DNA Methyltransferase
DNA Repair Enzymes
Phenotype
Neoplasms
Mutation
Health
Rectal Neoplasms
Epigenomics
Colonic Neoplasms
Cohort Studies
Biomarkers
Immunohistochemistry
Nurses

Keywords

  • Clinical outcome
  • Colon cancer
  • Epigenetics
  • Hypermethylation
  • MGMT

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers. / Shima, Kaori; Morikawa, Teppei; Baba, Yoshifumi; Nosho, Katsuhiko; Suzuki, Maiko; Yamauchi, Mai; Hayashi, Marika; Giovannucci, Edward; Fuchs, Charles S.; Ogino, Shuji.

In: Cancer Causes and Control, Vol. 22, No. 2, 01.02.2011, p. 301-309.

Research output: Contribution to journalArticle

Shima, K, Morikawa, T, Baba, Y, Nosho, K, Suzuki, M, Yamauchi, M, Hayashi, M, Giovannucci, E, Fuchs, CS & Ogino, S 2011, 'MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers', Cancer Causes and Control, vol. 22, no. 2, pp. 301-309. https://doi.org/10.1007/s10552-010-9698-z
Shima, Kaori ; Morikawa, Teppei ; Baba, Yoshifumi ; Nosho, Katsuhiko ; Suzuki, Maiko ; Yamauchi, Mai ; Hayashi, Marika ; Giovannucci, Edward ; Fuchs, Charles S. ; Ogino, Shuji. / MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers. In: Cancer Causes and Control. 2011 ; Vol. 22, No. 2. pp. 301-309.
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AU - Shima, Kaori

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AU - Baba, Yoshifumi

AU - Nosho, Katsuhiko

AU - Suzuki, Maiko

AU - Yamauchi, Mai

AU - Hayashi, Marika

AU - Giovannucci, Edward

AU - Fuchs, Charles S.

AU - Ogino, Shuji

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N2 - Objective: O 6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme. MGMT promoter hypermethylation and epigenetic silencing often occur as early events in carcinogenesis. However, prognostic significance of MGMT alterations in colorectal cancer remains uncertain. Methods: Utilizing a database of 855 colon and rectal cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected MGMT promoter hypermethylation in 325 tumors (38%) by MethyLight and loss of MGMT expression in 37% (247/672) of tumors by immunohistochemistry. We assessed the CpG island methylator phenotype (CIMP) using eight methylation markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and LINE-1 (L1) hypomethylation, TP53 (p53), and microsatellite instability (MSI). Results: MGMT hypermethylation was not associated with colorectal cancer-specific mortality in univariate or multivariate Cox regression analysis [adjusted hazard ratio (HR) = 1.03; 95% confidence interval (CI), 0.79-1.36] that adjusted for clinical and tumor features, including CIMP, MSI, and BRAF mutation. Similarly, MGMT loss was not associated with patient survival. MGMT loss was associated with G>A mutations in KRAS (p = 0.019) and PIK3CA (p = 0.0031). Conclusions: Despite a well-established role of MGMT aberrations in carcinogenesis, neither MGMT promoter methylation nor MGMT loss serves as a prognostic biomarker in colorectal cancer.

AB - Objective: O 6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme. MGMT promoter hypermethylation and epigenetic silencing often occur as early events in carcinogenesis. However, prognostic significance of MGMT alterations in colorectal cancer remains uncertain. Methods: Utilizing a database of 855 colon and rectal cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected MGMT promoter hypermethylation in 325 tumors (38%) by MethyLight and loss of MGMT expression in 37% (247/672) of tumors by immunohistochemistry. We assessed the CpG island methylator phenotype (CIMP) using eight methylation markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and LINE-1 (L1) hypomethylation, TP53 (p53), and microsatellite instability (MSI). Results: MGMT hypermethylation was not associated with colorectal cancer-specific mortality in univariate or multivariate Cox regression analysis [adjusted hazard ratio (HR) = 1.03; 95% confidence interval (CI), 0.79-1.36] that adjusted for clinical and tumor features, including CIMP, MSI, and BRAF mutation. Similarly, MGMT loss was not associated with patient survival. MGMT loss was associated with G>A mutations in KRAS (p = 0.019) and PIK3CA (p = 0.0031). Conclusions: Despite a well-established role of MGMT aberrations in carcinogenesis, neither MGMT promoter methylation nor MGMT loss serves as a prognostic biomarker in colorectal cancer.

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