DNA Repair and Cell Cycle Control Genes and the Risk of Young-Onset Lung Cancer

Abstract

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 À7C>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.

Multicenter analysis of lung cancer patients younger than 45 years in Shanghai

“…This hypothesis has been demonstrated in a few recent studies, looking at the association between early onset lung cancer and genes involved in xenobiotic metabolizing enzymes 24 and DNA repair. 25,26 We are beginning to examine the influence of genetic background in Chinese young lung cancer patients. Compared with squamous cell cancer, more patients with adenocarcinoma harbor mutations of the epidermal growth factor receptor (EGFR), which is highly sensitive to EGFR tyrosine kinase inhibitors.…”

Genetic Variants of NBS1 Predict Clinical Outcome of Platinum-based Chemotherapy in Advanced Non-small Cell Lung Cancer in Chinese

“…Publications on NBS1 polymorphisms have mainly focused on rs1805794 and the risk of cancers including lung, breast, bladder, renal cell cancers, non-Hodgkin lymphoma and childhood acute leukemia (Medina et al, 2003;Lan et al, 2005;Zienolddiny, 2005;Landi et al, 2006;Ryk et al, 2006;Hsu et al, 2007;Choudhury et al, 2008;Margulis et al, 2008;Mosor et al, 2008;Schuetz et al, 2009;Stern et al, 2009;Park et al, 2010), but the results were not consistent. A recent meta-analysis on rs1805794 has shed light on a positive association between the variant genotype of rs1805794 and the risk of multiple cancers (MeiXia et al, 2009).…”

Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in the Cypriot population

“…The genetic variants were selected based on three main criteria: (1) all SNPs chosen belong to genes that interact with either BRCA1 or BRCA2; (2) the SNPs chosen are either functional SNPs (based on potential protein changes, evolutionary conservation and location in putative functional regions [23][24][25] or (3) SNPs which were reported by other groups to modify cancer risk [14,[26][27][28][29][30][31][32]. For MRE11A and RAD50, we genotyped the tagging SNPs in Allen-Brady et al [33], and for NBS1, we genotyped the tagging SNPs in Lu et al [32].…”