MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: Indications for distinct pathways and sequence of events

S. de Vogel, M. P. Weijenberg, J. G. Herman, K. A D Wouters, A. F P M de Goeij, P. A. van den Brandt, A. P. de Bruïne, M. van Engeland

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1216-1222
Number of pages7
JournalAnnals of Oncology
Volume20
Issue number7
DOIs
StatePublished - 2009

Keywords

  • APC
  • BRAF
  • CRC
  • KRAS mutations
  • MGMT methylation
  • MLH1 methylation

ASJC Scopus subject areas

  • Oncology
  • Hematology

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