DNA repair and cell cycle control genes and the risk of young-onset lung cancer.
Exposure to tobacco smoke and to mutagenic xenobiotics can cause various types of DNA damage in lung cells, which, if not corrected by DNA repair systems, may lead to deregulation of the cell cycle and, ultimately, to cancer. Genetic variation could thus be an important factor in determining susceptibility to tobacco-induced lung cancer with genetic susceptibility playing a larger role in young-onset cases compared with that in the general population. We have therefore studied 102 single-nucleotide polymorphisms (SNP) in 34 key DNA repair and cell cycle control genes in 299 lung cancer cases diagnosed before the age of 50 years and 317 controls from six countries of Central and Eastern Europe. We have found no association of lung cancer risk with polymorphisms in genes related to cell cycle control, single-strand/double-strand break repair, or base excision repair. Significant associations (P < 0.05) were found with polymorphisms in genes involved in DNA damage sensing (ATM) and, interestingly, in four genes encoding proteins involved in mismatch repair (LIG1, LIG3, MLH1, and MSH6). The strongest associations were observed with heterozygote carriers of LIG1 -7C>T [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.13-2.64] and homozygote carriers of LIG3 rs1052536 (OR, 2.05; 95% CI, 1.25-3.38). Consideration of the relatively large number of markers assessed diminishes the significance of these findings; thus, these SNPs should be considered promising candidates for further investigation in other independent populations.
Landi
Stefano
S
Dip. Biologia-Genetics, University of Pisa, Pisa, Italy.
Gemignani
Federica
F
Canzian
Federico
F
Gaborieau
Valérie
V
Barale
Roberto
R
Landi
Debora
D
Szeszenia-Dabrowska
Neonilia
N
Zaridze
David
D
Lissowska
Jolanta
J
Rudnai
Peter
P
Fabianova
Eleonora
E
Mates
Dana
D
Foretova
Lenka
L
Janout
Vladimir
V
Bencko
Vladimir
V
Gioia-Patricola
Lydie
L
Hall
Janet
J
Boffetta
Paolo
P
Hung
Rayjean J
RJ
Brennan
Paul
P
D000328:Adult; D000367:Age Factors; D016022:Case-Control Studies; D004260:DNA Repair; D005061:Europe, Eastern / Q000453:epidemiology; D005260:Female; D018816:Genes, cdc; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged