Variants in folate pathway genes as modulators of genetic instability and lung cancer risk.
Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK.
Piskac-Collier
Amanda L
AL
Division of Cancer Prevention, Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Monroy
Claudia
C
Lopez
Mirtha S
MS
Cortes
Andrea
A
Etzel
Carol J
CJ
Greisinger
Anthony J
AJ
Spitz
Margaret R
MR
El-Zein
Randa A
RA
D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005492:Folic Acid / Q000235:genetics* / Q000378:metabolism*; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D015162:Micronucleus Tests; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D014407:Tumor Cells, Cultured
D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D012696:Glycine Hydroxymethyltransferase