To the editor: Although the existence of the CpG island methylator phenotype (CIMP) in colorectal cancer may be controversial, we were disappointed that the review by Agrawal et al of DNA methylation in breast and colorectal cancer1 did not cite recent studies that support CIMP. Although all studies of colon cancer have not reported the same associations with CIMP, there has been remarkable unanimity with respect to a very strong relationship with the BRAF V600E mutation. This relationship is independent of microsatellite instability and has been observed using different techniques and CpG islands to evaluate CIMP.2, 3, 4 Also, a significant relationship between CIMP and cigarette smoking independent of microsatellite instability has been seen;5 this relationship to an epidemiologic risk factor also supports CIMP as a true phenotype.
With regard to hereditary nonpolyposis colorectal cancer (HNPCC), it is somewhat misleading to state that ‘ … aberrant methylation of the mismatch repair genes, … hMLH1 or hMLH2, are the basis for the cancer (in hereditary non-polyposis colorectal cancer).’ The overwhelming percentage of cases of HNPCC is the result of a germ-line mutation and a subsequent somatic second hit (usually mutation) in one of the mismatch repair genes; germ-line methylation is an extremely rare cause of this syndrome.
References
Agrawal A, Murphy RF, Agrawal DK . DNA methylation in breast and colorectal cancers. Mod Pathol 2007;20:711–721.
Samowitz WS, Albertsen H, Herrick J, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 2005;129:837–845.
Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006;38:787–793.
Ogino S, Kawasaki T, Kirkner GJ, et al. Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagn 2007;9:305–314.
Samowitz WS, Albertsen H, Sweeney C, et al. Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst 2006;98:1731–1738.
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Samowitz, W., Ogino, S. Letter to the Editor. Mod Pathol 21, 1054 (2008). https://doi.org/10.1038/modpathol.2008.18
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DOI: https://doi.org/10.1038/modpathol.2008.18
