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 journalArticle

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

Fingerprint

Methyltransferases
Methylation
Colorectal Neoplasms
Mutation
DNA
Genes
Neoplasms
Gene Silencing

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

de Vogel, S., Weijenberg, M. P., Herman, J. G., Wouters, K. A. D., de Goeij, A. F. P. M., van den Brandt, P. A., ... van Engeland, M. (2009). MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: Indications for distinct pathways and sequence of events. Annals of Oncology, 20(7), 1216-1222. https://doi.org/10.1093/annonc/mdn782

MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer : Indications for distinct pathways and sequence of events. / de Vogel, S.; Weijenberg, M. P.; Herman, J. G.; Wouters, K. A D; de Goeij, A. F P M; van den Brandt, P. A.; de Bruïne, A. P.; van Engeland, M.

In: Annals of Oncology, Vol. 20, No. 7, 2009, p. 1216-1222.

Research output: Contribution to journalArticle

de Vogel, S, Weijenberg, MP, Herman, JG, Wouters, KAD, de Goeij, AFPM, van den Brandt, PA, de Bruïne, AP & van Engeland, M 2009, 'MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: Indications for distinct pathways and sequence of events', Annals of Oncology, vol. 20, no. 7, pp. 1216-1222. https://doi.org/10.1093/annonc/mdn782
de Vogel, S. ; Weijenberg, M. P. ; Herman, J. G. ; Wouters, K. A D ; de Goeij, A. F P M ; van den Brandt, P. A. ; de Bruïne, A. P. ; van Engeland, M. / MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer : Indications for distinct pathways and sequence of events. In: Annals of Oncology. 2009 ; Vol. 20, No. 7. pp. 1216-1222.
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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.",
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TY - JOUR

T1 - MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer

T2 - Indications for distinct pathways and sequence of events

AU - de Vogel, S.

AU - Weijenberg, M. P.

AU - Herman, J. G.

AU - Wouters, K. A D

AU - de Goeij, A. F P M

AU - van den Brandt, P. A.

AU - de Bruïne, A. P.

AU - van Engeland, M.

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - APC

KW - BRAF

KW - CRC

KW - KRAS mutations

KW - MGMT methylation

KW - MLH1 methylation

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U2 - 10.1093/annonc/mdn782

DO - 10.1093/annonc/mdn782

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C2 - 19164452

AN - SCOPUS:67650385667

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JO - Annals of Oncology

JF - Annals of Oncology

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