Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Annals of oncology, 2009-07, Vol.20 (7), p.1216-1222

Ort / Verlag

Oxford: Elsevier Ltd

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.