O6-methylguanine-DNA methyltransferase promoter hypermethylation in colorectal carcinogenesis.
Epigenetic alterations have been reported in colorectal neoplasia which can either complement or in some cases be predisposed to genetic alterations such as K-ras mutations. We examined the promoter methylation status of the CDKN2A and O6-methylguanine-DNA methyltransferase (MGMT) genes, after sodium bisulfite conversion and DNA amplification with methylation specific PCR. Moreover, we searched for G to A transitions in codons 12 and 13 of the K-ras oncogene in normal colorectal mucosae, aberrant crypt foci (ACF, early premalignant lesions) and carcinomas. CDKN2A hypermethylation was an infrequent event in ACF (2 of 26, 7.7%). On the contrary, MGMT hypermethylation was found in the normal mucosae (3 of the 12 samples, 25%), in 14 of the 26 ACF (53.8%) and in 7 of the 9 (77.8%) carcinomas examined. K-ras mutations were evident in 6 ACF (23%) and in 3 carcinomas (33.3%), mostly associated with MGMT promoter hypermethylation. These findings strongly support the hypothesis that epigenetic mechanisms play an important role in the early steps of colorectal carcinogenesis.
Menigatti
Mirco
M
DKBW, University of Modena and Reggio Emilia, Modena, Italy. mirco.menigatti@unibas.ch
Pedroni
Monica
M
Verrone
Anna Maria
AM
Borghi
Francesca
F
Scarselli
Alessandra
A
Benatti
Piero
P
Losi
Lorena
L
Di Gregorio
Carmela
C
Schär
Primo
P
Marra
Giancarlo
G
Ponz de Leon
Maurizio
M
Roncucci
Luca
L
D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D013447:Sulfites / Q000737:chemistry
D019941:Cyclin-Dependent Kinase Inhibitor p16; D013447:Sulfites; D019853:O(6)-Methylguanine-DNA Methyltransferase; C009279:sodium bisulfite