title: MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers.
abstract: OBJECTIVE
  O⁶-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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Maiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Marika
authors.initials: M
authors.lastname: Hayashi
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics; D019175:DNA Methylation / Q000502:physiology*; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D025521:Tumor Suppressor Proteins / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes