A multivariable logistic regression analysis for lung cancer risk.

<p>A multivariable logistic regression analysis for lung cancer risk.</p

A Newfound Association between <i>MDC1</i> Functional Polymorphism and Lung Cancer Risk in Chinese

<div><p>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 <i>MDC1</i> 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 <i>MDC1</i> 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 <i>MDC1</i> was significantly associated with lung cancer risk in both populations (<i>P</i> = 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 <i>MDC1</i> as a susceptible gene for lung cancer (<i>P</i> = 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 (<i>P</i> = 0.002). Our data suggested that the SNP rs4713354A>C of <i>MDC1</i> may be a functional genetic biomarker for susceptibility to lung cancer in Chinese.</p></div

Stratification analysis of the <i>MDC1</i> rs4713354A>C genotypes by selected variables in cases and controls.

a<p>ORs were adjusted for age, sex, smoking status, drinking status, and family history of cancer.</p>b<p><i>P</i> value of Breslow-Day test.</p>c<p><i>P</i> value of test for the multiplicative interaction.</p><p>Stratification analysis of the <i>MDC1</i> rs4713354A>C genotypes by selected variables in cases and controls.</p

Distribution of genotypes of <i>MDC1</i> and associations with the risk of lung cancer.

a<p>The genotype distributions of above SNPs in controls were all in Hardy-Weinberg equilibrium (<i>P</i>>0.05).</p>b<p>The frequency distribution of genotypes of SNPs between cases and controls by the chi-square test.</p>c<p>Adjusted in a logistic regression model that included age, sex, smoking status, drinking status, and family history of cancer.</p><p>Distribution of genotypes of <i>MDC1</i> and associations with the risk of lung cancer.</p

Functional Genetic Polymorphisms in PP2A Subunit Genes Confer Increased Risks of Lung Cancer in Southern and Eastern Chinese

<div><p>Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and functions as a tumor suppressor that negatively regulates the activity of some oncogenic kinases. Recent studies have reported that PP2A expression was suppressed during lung carcinogenesis, we there hypothesized that the single nucleotide polymorphisms (SNPs) in PP2A subunit genes may affect PP2A function and thus contribute to lung cancer susceptibility. In a two-stage case-control study with a total of 1559 lung cancer patients and 1679 controls, we genotyped eight putative functional SNPs and one identified functional SNP (i.e., rs11453459) in seven major PP2A subunits (i.e., <i>PPP2R1A</i>, <i>PPP2R1B</i>, <i>PPP2CA</i>, <i>PPP2R2A</i>, <i>PPP2R2B</i>, <i>PPP2R5C</i>, <i>PPP2R5E</i>) in southern and eastern Chinese. We found that rs11453459G (-G/GG) variant genotypes of <i>PPP2R1A</i> and the rs1255722AA variant genotype of <i>PPP2R5E</i> conferred increased risks of lung cancer (rs11453459, -G/GG vs. –: OR = 1.31, 95% CI = 1.13–1.51; rs1255722, AA vs. AG/GG: OR = 1.27, 95% CI = 1.07–1.51). After combined the two variants, the number of the adverse genotypes was positively associated with lung cancer risk in a dose-response manner (<i>P</i>_trend  = 5.63×10⁻⁶). Further functional assay showed that lung cancer tissues carrying rs1255722AA variant genotype had a significantly lower mRNA level of PPP2R5E compared with tissues carrying GG/GA genotypes. However, such effect was not observed for the other SNPs and other combinations. Our findings suggested that the two functional variants in <i>PPP2R1A</i> and <i>PPP2R5E</i> and their combination are associated with lung cancer risk in Chinese, which may be valuable biomarkers to predict risk of lung cancer.</p></div

Stratification analysis of the association between number of risk genotypes and lung cancer risk by selected variables.

a<p>Compared with 0 risk genotype, ORs were adjusted for age, sex, smoking status, alcohol use, and family history of cancer in a logistic regression models.</p>b<p>Trend test for lung cancer risk, with number of risk genotypes in each stratum.</p>c<p>Interaction test P value.</p

Frequency distribution of the SNP rs11453459->G and rs1255722G >A and their associations with lung cancer risk.

a<p>The observed genotype frequencies among the controls were all in agreement with the Hardy-Weinberg equilibrium in both sets (<i>P</i>>0.05 for all).</p>b<p>Adjusted in a logistic regression model that included age, sex, smoking status, drinking status, and family history of cancer.</p>c<p>The merged set comprised the discovery set and the validate set.</p

The <i>MKK7</i> p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese

<div><p>Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology. In the current study, based on three independently retrospective studies of 5,016 lung cancer patients and 5,181 controls, we analyzed the associations between five rare polymorphisms (i.e., p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) in <i>MKK7</i> and lung cancer risk and prognosis. To decipher the precise mechanisms of <i>MKK7</i> rare variants on lung cancer, a series of biological experiments was further performed. We found that the <i>MKK7</i> p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis. Compared with Glu/Glu common genotype, the 116Lys rare variants (Lys/Glu/+ Lys/Lys) presented an adverse effect on lung cancer susceptibility (odds ratio [OR] = 3.29, 95% confidence interval [CI] = 2.70–4.01). These rare variants strengthened patients’ clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis. In addition, the patients with 116Lys variants also contributed to worse cancer prognosis than those carriers with Glu/Glu genotype (hazard ratio [HR] = 1.53, 95% CI = 1.32–1.78). Functional experiments further verified that the <i>MKK7</i> p.116Lys variants altered the expression of several cancer-related genes and thus affected lung cancer cells proliferation, tumor growth and metastasis <i>in vivo</i> and <i>in vitro</i>. Taken together, our findings proposed that the <i>MKK7</i> p.Glu116Lys rare polymorphism incurred a pernicious impact on lung cancer risk and prognosis through modulating expressions of a serial of cancer-related genes.</p></div

Associations between <i>MKK7</i> rare polymorphisms and lung cancer survival in the three populations.

<p>Associations between <i>MKK7</i> rare polymorphisms and lung cancer survival in the three populations.</p

Associations between <i>MKK7</i> rare polymorphisms and lung cancer risk.

<p>Associations between <i>MKK7</i> rare polymorphisms and lung cancer risk.</p