Intermediate Methylation Epigenotype and Its Correlation to KRAS Mutation in Conventional Colorectal Adenoma

Koichi Yagi, Hirokazu Takahashi, Kiwamu Akagi, Keisuke Matsusaka, Yasuyuki Seto, Hiroyuki Aburatani, Atsushi Nakajima, Atsushi Kaneda
2012 American Journal of Pathology  
A subset of colorectal cancer shows significant accumulation of aberrant promoter methylation. Previously, we developed two groups of methylation markers that classified colorectal cancer into three epigenotypes: i) high-, ii) intermediate-, and iii) lowmethylation epigenotypes. High-methylation epigenotype, with methylation of both group 1 and group 2 markers, correlates to BRAF-mutation( ؉ ). Intermediate-methylation epigenotype, with methylation of group 2 markers, but not group 1,
more » ... group 1, correlates to KRASmutation( ؉ ). To gain insight into epigenotype development in colorectal carcinogenesis, especially intermediate-methylation epigenotype and its correlation to KRAS-mutation( ؉ ) in adenoma, we analyzed methylation levels of group 1 and group 2 markers quantitatively by matrix assisted laser desorption ionization-time of flight mass spectrometry, in 51 adenomas, 13 aberrant crypt foci, and 26 normal mucosa samples, and we compared them to 149 previously analyzed colorectal cancer samples. Three serrated adenomas were all BRAF-mutation( ؉ ), showing great methylation of group 1 and group 2 markers, thus highmethylation epigenotype. Forty-eight conventional adenomas were not methylated in group 1 markers and were classified into two clusters with higher and lower methylation of group 2 markers, thus into intermediateand low-methylation epigenotypes, respectively. Ade-noma with intermediate-methylation epigenotype correlated to KRAS-mutation( ؉ ). Methylation levels of group 2 markers in adenoma were higher than aberrant crypt foci and normal samples, but similar to cancer. These data suggested that epigenotype development occur at an earlier stage than carcinoma formation, and already be completed at the adenoma stage. Intermediate methylation epigenotype and its correlation to KRAS-mutation( ؉ ) were developed in conventional adenoma. (Am J Pathol 2012, 180:616 -625; Colorectal cancer arises as a consequence of genetic alteration and epigenetic alteration. 1 Gene mutations (eg, KRAS, p53, and APC) are well-known genetic alterations that occurred in colorectal cancer, which were demonstrated in the model of "adenoma-carcinoma sequence" by Bert Vogelstein. 2 Epigenetic alteration, such as DNA methylation or loss of imprinting, is also important in colorectal carcinogenesis, and aberrant promoter methylation is a major epigenetic mechanism for gene silencing to be involved in the initiation and progression of cancer. 3,4 As for accumulation of aberrant methylation, Toyota et al 5 reported in 1999 that a subset of colorectal cancer shows significantly frequent CpG island methylation [ie, the so-called CpG island methylator phenotype (CIMP)]. CIMP ϩ colorectal cancer significantly correlates to microsatellite instability and BRAF mutation. 6 Colorectal adenoma is known as a precursor lesion of colorectal cancer. Serrated adenomas were reported to show CIMP ϩ and frequent BRAF mutation, and DNA methylation was thus considered to be an early event in the serrated pathway, which explains carcinogenesis
doi:10.1016/j.ajpath.2011.10.010 pmid:22115708 fatcat:fpumqiffpfcs5ahnwcjbznzfeq