title: Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability.
abstract: The significance of low-level DNA microsatellite instability (MSI-L) is not well understood. K-ras mutation is associated with MSI-L colorectal cancer and with the silencing of the DNA repair gene O-6-methylguanine DNA methyltransferase (MGMT) by methylation of its promoter region. MGMT methylation was studied in sporadic colorectal cancers stratified as DNA microsatellite instability-high (n = 23), MSI-L (n = 44), and microsatellite-stable (n = 23). Methylation-specific PCR was used to detect MGMT-promoter hypermethylation in 3 of 23 (13%) microsatellite instability-high, in 28 of 44 (64%) MSI-L, and in 6 of 23 (26%) microsatellite-stable cancers (P = 0.0001). K-ras was mutated in 20 of 29 (69%) methylated MSI-L cancers and in 2 of 15 (13%) unmethylated MSI-L cancers (P = 0.001), indicating a relationship between MGMT-methylation and mutation of K-ras. Loss of nuclear expression of MGMT was demonstrated immunohistochemically in 23 of 31 (74%) cancers with methylated MGMT and in 10 of 49 (20%) cancers with nonmethylated MGMT (P < 0.0001). Loss of expression of MGMT was also demonstrated in 9 of 31 serrated polyps. Silencing of MGMT may predispose to mutation by overwhelming the DNA mismatch repair system and occurs with greatest frequency in MSI-L colorectal cancers.
authors.affiliation: Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital Foundation, Clinical Research Centre, Queensland, Australia. vickiWh@qimr.edu.au
authors.forename: V L
authors.initials: VL
authors.lastname: Whitehall
authors.forename: M D
authors.initials: MD
authors.lastname: Walsh
authors.forename: J
authors.initials: J
authors.lastname: Young
authors.forename: B A
authors.initials: BA
authors.lastname: Leggett
authors.forename: J R
authors.initials: JR
authors.lastname: Jass
mesh_terms: D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D019853:O(6)-Methylguanine-DNA Methyltransferase