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[Cancer Research 61, 827-830, February 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Methylation of O–6-Methylguanine DNA Methyltransferase Characterizes a Subset of Colorectal Cancer with Low-level DNA Microsatellite Instability1

Vicki L. J. Whitehall2, Michael D. Walsh, Joanne Young, Barbara A. Leggett and Jeremy R. Jass

Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital Foundation, Clinical Research Centre [V. L. J. W., J. Y., B. A. L.], and Department of Pathology, University of Queensland [M. D. W., J. R. J.], Brisbane, Queensland, Australia

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.




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