Polymorphisms in TDG and MGMT genes - epidemiological and functional study in lung cancer patients from Poland.
Functional genetic polymorphisms of DNA repair genes are good candidates for cancer susceptibility markers. We studied two genes coding for proteins removing small DNA adducts by direct repair (MGMT), or mispaired DNA bases by base excision repair (TDG). The non-silent polymorphisms of MGMT (84:Phe, 143:Val, 178:Arg) and TDG (199:Ser, 367:Met), and the functional MGMT enhancer polymorphism, did not show any statistically significant association with lung cancer risk in our case-control analysis, but due to the relatively small number of individuals, strong conclusions on cancer risk association or lack thereof cannot be made. Sequencing of the TDG cDNA has not revealed any novel polymorphism, but did find an alternatively spliced mRNA missing exon 2. Our search for polymorphisms within the promoter-enhancer region of MGMT revealed three novel sequence variants. The functional significance of the previously published MGMT enhancer polymorphism (1099C->T) was assessed. The less frequent sequence variant of the enhancer was associated with a modest (16-64%), but statistically significant, increase of MGMT promoter-enhancer activity in the studied cell lines. This work points to the importance of studying the expression-regulating elements of genes, as they may contain functional polymorphisms with the potential for modulating risk of various diseases, including cancer.
Krześniak
M
M
Department of Tumor Biology, Center of Oncology, Maria Skłodowska-Curie Memorial Institute, 44-101 Gliwice, Poland.
Butkiewicz
D
D
Samojedny
A
A
Chorazy
M
M
Rusin
M
M
D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D018076:DNA, Complementary / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005091:Exons / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011044:Poland / Q000453:epidemiology; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics; D044502:Thymine DNA Glycosylase / Q000235:genetics*
D018076:DNA, Complementary; D012333:RNA, Messenger; D019853:O(6)-Methylguanine-DNA Methyltransferase; D044502:Thymine DNA Glycosylase