The Functional <i>TP53</i> rs1042522 and <i>MDM4</i> rs4245739 Genetic Variants Contribute to Non-Hodgkin Lymphoma Risk

<div><p>As a heterogeneous kind of malignances, Non-Hodgkin lymphoma (NHL) is the most common hematologic cancer worldwide with the significantly increased morbidity in China. Accumulated evidences demonstrated that oncoprotein MDM4 plays a crucial role in the TP53 tumor suppressor signaling pathway. An rs4245739 A>C polymorphism locating in the <i>MDM4</i> 3′-untranslated region creates a miR-191 target site and results in allele-specific MDM4 expression. In this study, we examined the association between this polymorphism as well as the <i>TP53</i> Arg72Pro (rs1042522 G>C) genetic variant and Non-Hodgkin Lymphoma (NHL) risk in a Chinese Han population. Genotypes were determined in 200 NHL cases and 400 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found significantly increased NHL risk among carriers of the <i>TP53</i> 72Pro allele compared with those with the 72Arg allele (<i>P</i> = 0.002 for the Pro/Pro genotype). We also observed a significantly decreased NHL risks among carriers of the <i>MDM4</i> rs4245739 C allele compared with those with the A allele in Chinese (<i>P</i> = 0.014 for the AC genotype). Stratified analyses revealed the associations between these SNPs and NHL risk are especially noteworthy in young or male individuals. Additionally, the associations are much pronounced in NHL patients with B-cell lymphomas or grade 3 or 4 disease. Our results indicate that the <i>TP53</i> Arg72Pro and the <i>MDM4</i> rs4245739 polymorphisms contribute to NHL susceptibility and support the hypothesis that genetic variants in the <i>TP53</i> pathway genes can act as important modifiers of NHL risk.</p></div

Distribution of selected characteristics among Non-Hodgkin Lymphoma cases and controls.

<p>Note: DLBCL: diffuse large B-cell lymphoma, FL: follicular lymphoma, MZL: marginal zone lymphoma, CLL: chronic lymphocytic leukemia, SLL: small lymphocytic lymphoma.</p>a<p>Two-sided χ² test.</p>b<p>Median age of cases is 50 years.</p><p>Distribution of selected characteristics among Non-Hodgkin Lymphoma cases and controls.</p

Associations between the <i>TP53</i> rs1042522 Arg72Pro and <i>MDM4</i> rs4245739 A>C genetic polymorphisms and Non-Hodgkin Lymphoma risk.

<p>Note: NHL: Non-Hodgkin Lymphoma, OR: odds ratio, 95%CI: 95% confidence interval, NC: not calculated.</p>a<p>Data were calculated by logistic regression, adjusted for sex and age.</p><p>Associations between the <i>TP53</i> rs1042522 Arg72Pro and <i>MDM4</i> rs4245739 A>C genetic polymorphisms and Non-Hodgkin Lymphoma risk.</p

Transient luciferase reporter gene expression assays with constructs containing different alleles of <i>MDM4</i> 3’-UTR region in SCLC H446 cells.

<p>H446 cells were cotransfected with pRL-SV40 to standardize transfection efficiency. Fold increase was measured by defining the activity of cells co-transfected with both pGL3-rs4245739A or pGL3-rs4245739Creporter construct and NC-RNAs as 1. All experiments were performed in triplicates at least in three independent transfection experiments and each value represents mean ± SD. *<i>P</i><0.05compared with each of the luciferase construct by <i>t</i>-tests. NC-RNA, negative control RNAs; SCLC, small cell lung cancer.</p

Distribution of selected characteristics among SCLC cases and controls.

<p>Note: SCLC, small cell lung cancer.</p><p>^aTwo-sided χ² test.</p><p>^bMedian ages of patients for Shandong set and Jiangsu set are 57 years.</p><p>^cClassified according to the Veterans’ Administration Lung Study Group.</p><p>Distribution of selected characteristics among SCLC cases and controls.</p

Association between <i>TP53</i> rs1042522 Arg72Pro variant and NHL risk stratified by selected variables.

<p>Note: NHL: Non-Hodgkin Lymphoma, OR: odds ratio, 95%CI: 95% confidence interval, NC: not calculated.</p>a<p>Number of case patients with genotype/number of control subjects with genotype.</p>b<p>Data were calculated by logistic regression, adjusted for sex and age, where it was appropriate.</p>c<p><i>P</i> values for gene-environment interaction were calculated using the multiplicative interaction term in SPSS software.</p><p>Association between <i>TP53</i> rs1042522 Arg72Pro variant and NHL risk stratified by selected variables.</p

Clinicopathologic features in 136 HCC patients treated with TACE.

<p>Clinicopathologic features in 136 HCC patients treated with TACE.</p

The levels of serum miRNAs were associated with overall survival.

<p><b>A.</b> Patients with low or high expression of miR-200a (Cutoff value: Delta CT = 16.02). <b>B.</b> Patients with low or high expression of miR-21 (Cutoff value: Delta CT = 6.08). <b>C.</b> Patients with low or high expression of miR-122 (Cutoff value: Delta CT = 6.88). <b>D.</b> Patients with low or high expression of miR-224-5p (Cutoff value: Delta CT = 14.22). <b>E.</b> The relative expression level of serum miR-200a, miR-21, miR-122 and miR-224-5p in the group of HCC patients with high expression level was normalized by the group of patients with low expression level (set as 1), respectively. Mean ± s.d.</p

Univariate and Multivariate Cox proportional hazards regression analysis of clinical parameters in relation to disease outcome.

<p>HR, hazard ratio; CI, confidence interval; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha-fetoprotein.</p><p>Univariate and Multivariate Cox proportional hazards regression analysis of clinical parameters in relation to disease outcome.</p

Association of clinical parameters with overall survival by Kaplan-Meier curves and the log-rank test.

<p><b>A.</b> AFP-normal, AFP-elevated or AFP-diagnostic patients. <b>B.</b> Patients with BCLC stages A+B or C. <b>C.</b> Patients with Child-Puge class A or B. <b>D.</b> Patients with or without satellite nodules. SN: satellite nodules.</p