title: MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer.
abstract: O-6-methylguanine-DNA methyltransferase (MGMT) repairs inappropriately methylated guanine residues in DNA. MGMT promoter methylation and gene silencing are common events in colorectal cancer, and may or may not co-exist with the CpG island methylator phenotype (CIMP). To date, no study has examined the relationship between MGMT promoter methylation and common MGMT single nucleotide polymorphisms (SNPs), which have been associated with colorectal cancer risk. Utilizing real-time polymerase chain reaction (MethyLight technology), we quantified DNA methylation in MGMT and eight other markers (a CIMP diagnostic panel including CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1 in 182 colorectal cancers collected from two prospective cohorts, the Nurses' Health Study and the Health Professionals Follow-up Study. We genotyped four MGMT germline SNPs in normal DNA and assessed microsatellite instability (MSI), 18q loss of heterozygosity and KRAS and BRAF status in tumors. The presence of a common MGMT promoter SNP (NM_002412.2:c.-56C>T) (rs16906252) was strongly associated with MGMT methylation (multivariate odds ratio 18.0; 95% confidence interval, 6.2-52.1, P < 0.0001). The presence of the c.-56C>T SNP was also associated with loss of MGMT expression in tumors (assessed by immunohistochemistry) (P = 0.009). This promoter SNP was not correlated with KRAS, BRAF, CIMP or MSI status. None of the other three non-promoter SNPs was significantly associated with any molecular changes tested. In conclusion, we have found a strong association between the germline polymorphism (c.-56C>T) of the MGMT promoter and promoter methylation/silencing of MGMT in colorectal cancer. Our data provide compelling evidence for common susceptibility for MGMT promoter CpG island methylation.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Aditi
authors.initials: A
authors.lastname: Hazra
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kirkner
authors.forename: Takako
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Suemoto
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000368:Aged; D002887:Chromosomes, Human, Pair 18; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D005819:Genetic Markers; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014481:United States
chemical_list: D004273:DNA, Neoplasm; D005819:Genetic Markers; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes