title: Sequence variants in cell cycle control pathway, X-ray exposure, and lung cancer risk: a multicenter case-control study in Central Europe.
abstract: Exposure to ionizing radiation (IR) results in various types of DNA damage and is a suspected cause of lung cancer. An essential cellular machinery against DNA damage is cell cycle control, which is regulated by several genes, including TP53, CCND1, and CDKN2A. Therefore, we hypothesized that the genetic variants in these three genes influence the predisposition of lung cancer (i.e., CCND1 G870A, CDKN2A Ala(148)Thr, TP53 Arg(72)Pro, and 16-bp repeat in intron 3) and that the effect of X-ray on lung cancer risk can be modified by the presence of these genetic variations. The study was conducted in 15 centers in 6 countries of Central Europe between 1998 and 2002. A total of 2,238 cases and 2,289 controls were recruited and provided DNA samples. Cases with positive family history were analyzed separately. The joint effect of X-ray and previous risk genotypes was assessed, and modification by sequence variants on X-ray dose-response relationship with lung cancer risk was evaluated. We found an overall effect of TP53 intron 3 16-bp repeats [odds ratio (OR), 1.99; 95% confidence interval (95% CI), 1.27-3.13], which was stronger among cases with family history of lung cancer (OR, 2.98; 95% CI, 1.29-6.87). In addition, our results suggested an interaction that was greater than multiplicativity between TP53 intron 3 16-bp repeats and multiple X-ray exposures (interaction OR, 5.69; 95% CI, 1.33-24.3). We did not observe a main effect of CCND1 G870A polymorphism; however, the dose-response relationship between lung cancer risk and X-ray exposures was modified by CCND1 genotype with no risk from X-ray exposures among subjects who carried G/G genotype, intermediate risk [trend OR for X-ray, 1.16; 95% CI, 1.05-1.27) among subjects with G/A genotype, and highest risk [trend OR for X-ray, 1.29; 95% CI, 1.12-1.49) among subjects with A/A genotype. Sequence variants in cell cycle control pathway may increase the risk of lung cancer and modify the risk conferred by multiple X-ray exposures. However, a definite conclusion can only be drawn on replication by different studies among individuals who are highly exposed to IR.
authors.affiliation: IARC, Lyon, France.
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Norman
authors.initials: N
authors.lastname: Moullan
authors.forename: Neonila
authors.initials: N
authors.lastname: Szeszenia-Dabrowska
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Peter
authors.initials: P
authors.lastname: Rudnai
authors.forename: Eleonora
authors.initials: E
authors.lastname: Fabianova
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.forename: Lenka
authors.initials: L
authors.lastname: Foretova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bencko
authors.forename: Amelie
authors.initials: A
authors.lastname: Chabrier
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.forename: Janet
authors.initials: J
authors.lastname: Hall
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
mesh_terms: D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics* / Q000528:radiation effects; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007407:Interviews as Topic; D008175:Lung Neoplasms / Q000097:blood / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D011044:Poland / Q000453:epidemiology; D014965:X-Rays / Q000009:adverse effects*
chemical_list: D056741:Cyclin D; D016213:Cyclins