Association between single nucleotide polymorphisms in the PI3K/AKT/mTOR pathway and bladder cancer risk in a sample of Iranian population

Abstract

In the past few years several investigations have focused on the role of PI3K/AKT/mTOR pathway and its deregulations in different cancers. This study aimed to examine genetic polymorphisms of this pathway in bladder cancer (BC). In this case-control study, 235 patients with pathologically confirmed bladder cancer and 254 control subjects were examined. PIK3CA, AKT1 and mTOR variants were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The findings proposed that the PIK3CA rs6443624 SNP significantly decreased the risk of BC (OR=0.44, 95 % CI=0.30-0.65, p<0.0001 CA vs CC; OR=0.35, 95 % CI=0.16-0.78, p=0.0107, AA vs CC; OR=0.60, 95 % CI=0.46-0.79, p=0.0002, A vs T). The AKT1 rs2498801 variant is associated with a decreased risk of BC (OR=0.57, 95 % CI=0.39-0.82, p=0.003, AG vs AA; OR=0.74, 95 % CI=0.56-0.97, p=0.032, G vs A) while, AKT1 rs1130233 polymorphism considerably increased the risk of BC (OR=3.70, 95 % CI=2.52-5.43, p<0.0001, GA vs GG; OR=5.81, 95 % CI=1.53-21.97, p=0.010, AA vs GG; OR=2.71, 95 % CI=1.98-3.70, p<0.0001, A vs G). Additionally, mTOR rs2295080 variant notably increased the risk of BC (OR=2.25, 95 % CI=1.50-3.38, p<0.0001, GT vs GG; OR=4.75, 95 % CI=2.80-8.06, p<0.0001, TT vs GG; OR=3.10, 95 % CI=2.34-4.10, p<0.0001, T vs G). None of the other examined polymorphisms (AKT1 rs1130214, AKT1 rs3730358, mTOR rs1883965) revealed significant association with BC. In conclusion, our findings suggest that PIK3CA rs6443624, AKT1 rs2498801, AKT1 rs1130233, as well mTOR rs2295080 polymorphism may be related to bladder cancer development in a sample of Iranian population. Validation of our findings in larger sample sizes of different ethnicities would provide evidence on the role of variants of PI3K/AKT/mTOR pathway in developing BC.

Keywords: AKT1; PIK3CA; bladder cancer; mTOR; polymorphism.

Table 1. Demographic and clinicopathological characteristics of bladder cancer patients and control subjects

Table 2. The primers used for detection of PI3K/AKT/mTOR polymorphisms

Table 3. Genotype and allele frequencies of miRNAs polymorphisms in bladder cancer and controls

Figure 1. Photograph of electrophoresis pattern of the PCR-RFLP method for detection of PIK3CA rs6443624 (A), PIK3CA rs141178472 (B), AKT1 rs2498801 (C), AKT1 rs1130233 (D), AKT1 rs1130214 (E), AKT1 rs3730358 (F), mTOR rs1883965 (G), and mTOR rs2295080 (H). M: DNA marker. For PIK3CA rs6443624, lanes 1, 4, and 7: CA; lanes 2, 5, and 8: CC; lanes 3, and 6: AA. For PIK3CA rs141178472, all lanes are TT. For AKT1 rs2498801, lanes 1, and 4: AG; lanes 2, and 5: GG; lanes 3, and 6: AA. Regarding AKT1 rs1130233, lanes 1, 4, and 6: GA; lanes 1, 5, and 8: GG; lanes 3, and 6: AA. For AKT1 rs1130214, lanes 1, 4 and 7: TG; lanes 2, 5, and 8: GG; lanes 3, and 6: TT. For AKT1 rs3730358, lanes 1, 4, 6, and 7: TC; lanes 2, 5, and 8: CC; lane 3: TT. For mTOR rs1883965, lanes 1, 4, and 7: AG; lanes 2, 5, and 8: GG; lanes 3, and 6: AA. For mTOR rs2295080, lanes 1, 4, and 7: TG; lanes 2, 5, and 8: GG; lanes 3, and 6: TT.