Sequence variants in cell cycle control pathway, x-ray exposure, and lung cancer risk: A multicenter case-control study in Central Europe

Rayjean J. Hung, Paolo Boffetta, Federico Canzian, Norman Moullan, Neonila Szeszenia-Dabrowska, David Zaridze, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Lenka Foretova, Vladimir Janout, Vladimir Bencko, Amelie Chabrier, Stefano Landi, Federica Gemignani, Janet Hall, Paul Brennan

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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, CCNDl, and CDKN2A. Therefore, we hypothesized that the genetic variants in these three genes influence the predisposition of lung cancer (i.e., CCND1 G870A, CDKN2A Ala148ThT, TP53 Arg72Pro, 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 nuiltiplicativity 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 GIG 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.

Original languageEnglish
Pages (from-to)8280-8286
Number of pages7
JournalCancer Research
Volume66
Issue number16
DOIs
Publication statusPublished - Aug 15 2006

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hung, R. J., Boffetta, P., Canzian, F., Moullan, N., Szeszenia-Dabrowska, N., Zaridze, D., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Foretova, L., Janout, V., Bencko, V., Chabrier, A., Landi, S., Gemignani, F., Hall, J., & Brennan, P. (2006). Sequence variants in cell cycle control pathway, x-ray exposure, and lung cancer risk: A multicenter case-control study in Central Europe. Cancer Research, 66(16), 8280-8286. https://doi.org/10.1158/0008-5472.CAN-05-3099