Annals of Oncology Advance Access originally published online on January 22, 2009
Annals of Oncology 2009 20(7):1216-1222; doi:10.1093/annonc/mdn782
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gastrointestinal tumors |
MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: indications for distinct pathways and sequence of events
1 Department of Epidemiology, GROW—School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
2 Department of Pathology, GROW—School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
3 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, USA
* Correspondence to: Dr M. van Engeland, Department of Pathology, GROW—School for Oncology and Developmental Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. Tel: +31-43-3874622; Fax: +31-43-3876613; E-mail: m.vanengeland{at}path.unimaas.nl
Background: To study how caretaker gene silencing relates to gatekeeper mutations in colorectal cancer (CRC), we investigated whether O6-methylguanine DNA methyltransferase (MGMT) and Human Mut-L Homologue 1 (MLH1) promoter hypermethylation are associated with APC, KRAS and BRAF mutations among 734 CRC patients.
Methods: We compared MGMT hypermethylation with G:C > A:T mutations in APC and KRAS and with the occurrence of such mutations in CpG or non-CpG dinucleotides in APC. We also compared MLH1 hypermethylation with truncating APC mutations and activating KRAS and BRAF mutations.
Results: Only 10% of the tumors showed both MGMT and MLH1 hypermethylation. MGMT hypermethylation occurred more frequently in tumors with G:C > A:T KRAS mutations (55%) compared with those without these mutations (38%, P < 0.001). No such difference was observed for G:C > A:T mutations in APC, regardless of whether mutations occurred in CpG or non-CpG dinucleotides. MLH1 hypermethylation was less common in tumors with APC mutations (P = 0.006) or KRAS mutations (P = 0.001), but was positively associated with BRAF mutations (P < 0.001).
Conclusions: MGMT hypermethylation is associated with G:C > A:T mutations in KRAS, but not in APC, suggesting that MGMT hypermethylation may succeed APC mutations but precedes KRAS mutations in colorectal carcinogenesis. MLH1-hypermethylated tumors harbor fewer APC and KRAS mutations and more BRAF mutations, suggesting that they develop distinctly from an MGMT methylator pathway.
Key words: APC, BRAF, KRAS mutations, CRC, MGMT methylation, MLH1 methylation
Received for publication September 13, 2008. Revision received December 11, 2008. Accepted for publication December 12, 2008.