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

@article{citeulike:4306707, abstract = {BACKGROUND: To study how caretaker gene silencing relates to gatekeeper mutations in colorectal cancer (CRC), we investigated whether O(6)-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.}, author = {de Vogel, S and Weijenberg, M P P. and Herman, J G G. and Wouters, K A D A. and de Goeij, A F P M F. and van den Brandt, P A A. and de Bru\"{i}ne, A P P. and van Engeland, M}, citeulike-article-id = {4306707}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/19164452}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=19164452}, day = {22}, issn = {1569-8041}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology / ESMO}, keywords = {apc, colon\_cancer, kras, methylation}, month = {January}, posted-at = {2009-04-14 11:54:23}, priority = {2}, title = {MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: indications for distinct pathways and sequence of events.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/19164452}, year = {2009} }

TY - JOUR ID - citeulike:4306707 L3 - citeulike-article-id:4306707 N2 - BACKGROUND: To study how caretaker gene silencing relates to gatekeeper mutations in colorectal cancer (CRC), we investigated whether O(6)-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. JF - Annals of oncology : official journal of the European Society for Medical Oncology / ESMO SN - 1569-8041 TI - MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: indications for distinct pathways and sequence of events. KW - apc KW - colon_cancer KW - kras KW - methylation 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 - 2009/01/22/ UR - http://view.ncbi.nlm.nih.gov/pubmed/19164452 ER -