Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk.
Single nucleotide polymorphisms (SNPs) were searched for in 36 genes involved in diverse DNA repair pathways, and 50 nonsynonymous (associated with amino acid changes) SNPs identified were assessed for associations with lung cancer risk by a case-control study consisting of 752 adenocarcinoma cases, 250 squamous cell carcinoma cases and 685 controls. An SNP, Arg72Pro, of the TP53 gene encoding a DNA damage response protein showed the strongest association with squamous cell carcinoma risk (OR Pro/Pro vs. Arg/Arg = 2.2), while 2 other SNPs, Phe257Ser of the REV gene encoding a translesion DNA polymerase and Ile658Val of the LIG4 gene encoding a DNA double-strand break repair protein, also showed associations (OR Ser/Ser vs. Phe/Phe = 2.0 and OR Ile/Val vs. Ile/Ile = 0.4, respectively). An SNP, Thr706Ala, in the POLI gene encoding another translesion DNA polymerase was associated with adenocarcinoma and squamous cell carcinoma risk, particularly in individuals of ages < 61 years (OR Ala/Ala + Ala/Thr vs. Thr/Thr = 1.5 and 2.4, respectively). POLI is the human counterpart of PolI, a strong candidate for the Par2 (pulmonary adenoma resistance 2) gene responsible for adenoma/adenocarcinoma susceptibility in mice. The present results suggest that these 4 SNPs function as genetic factors underlying lung cancer susceptibility by modulating activities to maintain the genome integrity of each individual.
Sakiyama
Tokuki
T
Center for Medical Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Kohno
Takashi
T
Mimaki
Sachiyo
S
Ohta
Tsutomu
T
Yanagitani
Noriko
N
Sobue
Tomotaka
T
Kunitoh
Hideo
H
Saito
Ryusei
R
Shimizu
Kimiko
K
Hirama
Chie
C
Kimura
Junko
J
Maeno
Go
G
Hirose
Hiroshi
H
Eguchi
Takashi
T
Saito
Daizo
D
Ohki
Misao
M
Yokota
Jun
J
D000230:Adenocarcinoma / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000596:Amino Acids / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D016022:Case-Control Studies; D004249:DNA Damage; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics*; D004256:DNA Polymerase I / Q000235:genetics*; D004260:DNA Repair; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D012907:Smoking; D000099270:Y-Family DNA Polymerases
D000596:Amino Acids; D000072481:DNA Ligase ATP; D011088:DNA Ligases; D004256:DNA Polymerase I; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; C000607893:LIG4 protein, human; C429004:REV1 protein, human; D000099270:Y-Family DNA Polymerases