Abstract
Mediator of DNA damage checkpoint protein 1 (MDC1) plays an early and core role in Double-Strand Break Repair (DDR) and ataxia telangiectasia-mutated (ATM) mediated response to DNA double-strand breaks (DSBs), and thus involves the pathogenesis of several DNA damage-related diseases such as cancer. We hypothesized that the single nucleotide polymorphisms (SNPs) of MDC1 which have potencies on affecting MDC1 expression or function were associated with risk of lung cancer. In a two-stage case-control study, we tested the association between 5 putatively functional SNPs of MDC1 and lung cancer risk in a southern Chinese population, and validated the promising association in an eastern Chinese population. We found the SNP rs4713354A>C that is located in the 5′-untranslated region of MDC1 was significantly associated with lung cancer risk in both populations (P = 0.024), with an odds ratio as 1.23(95% confidence interval = 1.35–1.26) for the rs4713354C (CA+CC) genotypes compared to the rs4713354AA genotype. However, no significant association was observed between other SNPs and lung cancer risk. The gene-based analysis rested with these SNPs suggested the MDC1 as a susceptible gene for lung cancer (P = 0.009). Moreover, by querying the gene expression database, we further found that the rs4713354C genotypes confer a significantly lower mRNA expression of MDC1 than the rs4713354AA genotype in 260 cases of lymphoblastoid cells (P = 0.002). Our data suggested that the SNP rs4713354A>C of MDC1 may be a functional genetic biomarker for susceptibility to lung cancer in Chinese.
Highlights
DNA damage response (DDR) is a sophisticated cellular procedure involving multiple molecules to repair DNA damage and maintain the genome integrity and fidelity
Association between Mediator of DNA damage checkpoint protein 1 (MDC1) single nucleotide polymorphisms (SNPs) and lung cancer risk Table 1 shows the frequency distribution of the five SNPs in cases and controls
The genotype distributions of all SNPs in the controls of southern Chinese were all in agreement with the Hardy-Weinberg equilibrium (P.0.05 for all)
Summary
DNA damage response (DDR) is a sophisticated cellular procedure involving multiple molecules to repair DNA damage and maintain the genome integrity and fidelity. DNA damage can be caused by tobacco carcinogens or ionizing radiation, or other sources, it triggers DDR including activation of cell cycle checkpoint, commencement of transcriptional programs, and execution of DNA repair, or initiation of apoptosis when the damage is severe [1,2,3]. DDR can protect the cellular DNA from damage by recruiting a series of DDR proteins that act as sensors, transducers, mediators and effectors in DDR. The transducers, aided by the mediators, amplify the signal and transmit it to the effectors, which carry out diverse roles such as repair, checkpoint activation and if necessary-apoptosis [4]
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