The relationship between 8-oxo-7,8-dihydro-2'-deoxyguanosine level and extent of cytosine methylation in leukocytes DNA of healthy subjects and in patients with colon adenomas and carcinomas.
It has been known for a long time that DNA hypomethylation occurs in many human cancers and precancerous conditions. However, the mechanisms of hypomethylation are largely unknown. It is possible that endogenous 8-oxo-7,8-dihydroguanine (8-oxoGua) level may be linked to aberrant DNA methylation of adjacent cytosine and in this way influences carcinogenesis. Therefore, the aim of the present study was to assess a possible link between 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) background level and 5-methylcytosine content in DNA from human leukocytes of healthy subjects (n=105) as well as in patients with colon adenomas (n=39) and carcinomas (n=50). Our results demonstrated statistically significant negative correlation between background level of 8-oxodG and 5-methylcytosine content in DNA isolated from leukocytes of healthy donors (r=-0.3436, p=0.0003). The mean content of 5-methylcytosine was significantly lower, while 8-oxodG level was significantly higher in leukocytes DNA of patients with colon adenomas and carcinomas in comparison with healthy subjects. The mean values for 5-methylcytosine were: 3.59+/-0.173% (healthy subjects), 3.38+/-0.128% (patients with adenomas), 3.40+/-0.208% (colon cancer patients). The mean values of 8-oxodG in DNA were, respectively: 4.67+/-1.276, 5.72+/-1.787, 5.76+/-1.884 8-oxodG per 10(6) dG molecules. DNA from affected tissue (colon) suffered from significant, about 10% reduction in cytosine methylation in comparison with leukocytes of the paired subjects. Our work provides the first in vivo evidence suggesting that increased levels of 8-oxodG in DNA may lead to carcinogenesis not only via mispair/mutagenic potential of the modified base but also through its ability to influence gene expression by affecting DNA methylation.
Guz
Jolanta
J
Department of Clinical Biochemistry, Collegium Medicum, Nicolaus Copernicus University, Karlowicza 24, 85-092 Bydgoszcz, Poland.
Foksinski
Marek
M
Siomek
Agnieszka
A
Gackowski
Daniel
D
Rozalski
Rafal
R
Dziaman
Tomasz
T
Szpila
Anna
A
Olinski
Ryszard
R
D044503:5-Methylcytosine / Q000378:metabolism*; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000236:Adenoma / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D003596:Cytosine / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged
D044503:5-Methylcytosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003596:Cytosine; D003849:Deoxyguanosine