Combined effects of genetic variants of the PTEN, AKT1, MDM2 and p53 genes on the risk of nasopharyngeal carcinoma.

Phosphatase and tensin homolog (PTEN), v-akt murine thymoma viral oncogene homolog 1 (AKT1), mouse double minute 2 (MDM2) and p53 play important roles in the development of cancer. We examined whether the single nucleotide polymorphisms (SNPs) in the PTEN, AKT1, MDM2 and p53 genes were related to the risk and severity of nasopharyngeal carcinoma (NPC) in the Chinese population. Seven SNPs [p53 rs1042522, PTEN rs11202592, AKT1 SNP1-5 (rs3803300, rs1130214, rs3730358, rs1130233 and rs2494732)] were genotyped in 593 NPC cases and 480 controls by PCR direct sequencing or PCR-RFLP analysis. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). None of the polymorphisms alone was associated with the risk or severity of NPC. However, haplotype analyses indicated that a two-SNP core haplotype (SNP4-5, AA) in AKT1 was associated with a significantly increased susceptibility to NPC risk (adjusted OR  =  3.87, 95% CI  =  1.96-7.65; P<0.001). Furthermore, there was a significantly increased risk of NPC associated with the combined risk genotypes (i.e., p53 rs1042522 Arg/Pro + Pro/Pro, MDM2 rs2279244 G/T + G/G, PTEN rs11202592 C/C, AKT1 rs1130233 A/A). Compared with the low-risk group (0-2 combined risk genotypes), the high-risk group (3-4 combined risk genotypes) was associated with a significantly increased susceptibility to NPC risk (adjusted OR  =  1.67, 95% CI  =  1.12-2.50; P = 0.012). Our results suggest that genetic variants in the PTEN, AKT1, MDM2 and p53 tumor suppressor-oncoprotein network may play roles in mediating the susceptibility to NPC in Chinese populations

Combined effects of the genetic variants in the <i>PTEN</i>, <i>AKT1</i>, <i>MDM2</i> and <i>p53</i> genes on the risk of nasopharyngeal carcinoma.

<p>Abbreviations: OR, odds ratio; CI, confidence interval.</p>a<p><i>χ²</i> test for the distribution of genotypes between patients and control subjects.</p>b<p><i>P</i> values were calculated by multivariate logistic regression, adjusted for age, sex, smoking and drinking status, smoking level, and nationality.</p>c<p><i>χ</i>² test for the <i>P</i>_trend value of genotypes between patients and control subjects.</p>d<p>Low-risk group, individuals carrying 0–2 risk genotypes; high-risk group, individuals carrying 3-4 risk genotypes.</p><p>*<i>P</i> value remained significant after c°rrection for multiple comparisons (<i>P</i> = 0.048).</p

Haplotypes of <i>AKT1</i> polymorphisms and the risk of nasopharyngeal carcinoma.

<p>(<i>a</i>) Genomic structure of the <i>AKT1</i> locus and the polymorphic sites used. Exons (boxes) and introns are not drawn to scale; open boxes represent noncoding sequences, and filled boxes represent coding sequences. The physical distance between SNPs is shown in nucleotides. (<i>b</i>) Linkage disequilibrium (LD) map of SNPs based on <i>D</i> ´. (<i>c</i>) LD map of SNPs based on <i>r</i>². (<i>d</i>) Global <i>P</i> values from single-locus and multi-locus (two to five) based association analysis. (<i>e</i>) Haplotypes showing significant genetic associations with the risk of nasopharyngeal carcinoma. The two-SNP core haplotype is highlighted in gray.</p

Stratification analysis of the combined genotypes of the <i>PTEN</i>, <i>AKT1</i>, <i>MDM2</i> and <i>p53</i> polymorphisms and risk of nasopharyngeal carcinoma.

<p>Abbreviations: OR, odds ratio; CI, confidence interval.</p>a<p>ORs and <i>P</i> values were calculated by multivariate logistic regression, adjusted for age, sex, smoking and drinking status, smoking level and nationality when appropriate within the strata.</p>b<p>For differences in ORs within each stratum.</p>c<p>Low-risk group, individuals carrying 0–2 risk genotypes; high-risk group, individuals carrying 3–4 risk genotypes.</p

Primers and restriction enzymes used to investigate polymorphisms in the <i>PTEN</i>, <i>AKT1</i> and <i>p53</i> genes.

a<p>Italicized lowercase letters indicate base mismatches.</p>b<p>Designated rs2498799 in previous literature.</p