Characterization and risk association of polymorphisms in Aurora kinases A, B and C with genetic susceptibility to gastric cancer development

Abstract

Background: Single nucleotide polymorphisms (SNPs) in genes encoding mitotic kinases could influence development and progression of gastric cancer (GC).

Methods: Case-control study of nine SNPs in mitotic genes was conducted using qPCR. The study included 116 GC patients and 203 controls. In silico analysis was performed to evaluate the effects of polymorphisms on transcription factors binding sites.

Results: The AURKA rs1047972 genotypes (CT vs. CC: OR, 1.96; 95% CI, 1.05-3.65; p = 0.033; CC + TT vs. CT: OR, 1.94; 95% CI, 1.04-3.60; p = 0.036) and rs911160 (CC vs. GG: OR, 5.56; 95% CI, 1.24-24.81; p = 0.025; GG + CG vs. CC: OR, 5.26; 95% CI, 1.19-23.22; p = 0.028), were associated with increased GC risk, whereas certain rs8173 genotypes (CG vs. CC: OR, 0.60; 95% CI, 0.36-0.99; p = 0.049; GG vs. CC: OR, 0.38; 95% CI, 0.18-0.79; p = 0.010; CC + CG vs. GG: OR, 0.49; 95% CI, 0.25-0.98; p = 0.043) were protective. Association with increased GC risk was demonstrated for AURKB rs2241909 (GG + AG vs. AA: OR, 1.61; 95% CI, 1.01-2.56; p = 0.041) and rs2289590 (AC vs. AA: OR, 2.41; 95% CI, 1.47-3.98; p = 0.001; CC vs. AA: OR, 6.77; 95% CI, 2.24-20.47; p = 0.001; AA+AC vs. CC: OR, 4.23; 95% CI, 1.44-12.40; p = 0.009). Furthermore, AURKC rs11084490 (GG + CG vs. CC: OR, 1.71; 95% CI, 1.04-2.81; p = 0.033) was associated with increased GC risk. A combined analysis of five SNPs, associated with an increased GC risk, detected polymorphism profiles where all the combinations contribute to the higher GC risk, with an OR increased 1.51-fold for the rs1047972(CT)/rs11084490(CG + GG) to 2.29-fold for the rs1047972(CT)/rs911160(CC) combinations. In silico analysis for rs911160 and rs2289590 demonstrated that different transcription factors preferentially bind to polymorphic sites, indicating that AURKA and AURKB could be regulated differently depending on the presence of particular allele.

Conclusions: Our results revealed that AURKA (rs1047972 and rs911160), AURKB (rs2241909 and rs2289590) and AURKC (rs11084490) are associated with a higher risk of GC susceptibility. Our findings also showed that the combined effect of these SNPs may influence GC risk, thus indicating the significance of assessing multiple polymorphisms, jointly. The study was conducted on a less numerous but ethnically homogeneous Bosnian population, therefore further investigations in larger and multiethnic groups and the assessment of functional impact of the results are needed to strengthen the findings.

Keywords: Cancer susceptibility; Chromosomal instability; Gastric cancer; Mitotic kinases; Single nucleotide polymorphisms.

Fig. 1

The locations of rs2273535, rs1047972, rs911160 and rs8173 polymorphisms in AURKA, rs2241909 and rs2289590 in AURKB, rs758099 and rs11084490 in AURKC and rs42873 in PLK1 mitotic checkpoint genes. White boxes: untranslated regions (UTRs). Orange boxes: protein coding regions. The black lines connecting boxes: introns. The gene structures were extracted from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB), GRCh38 Genome Assembly

Fig. 2

MAF values for polymorphisms rs2273535, rs1047972, rs911160 and rs8173 (AURKA), rs2241909 and rs2289590 (AURKB), rs758099 and rs11084490 (AURKC), and rs42873 (PLK1), in different populations. ALL: All individuals from 1000 Genome Project Phase 3 release. C: Studied Bosnian control population; CEU: Utah residents with Northern and Western European ancestry; EUR: European population; GC: Studied Bosnian gastric cancer population; MAF: Minor allele frequency. SNP: Single nucleotide polymorphism

Fig. 3

The linkage disequilibrium between polymorphisms in the AURKA gene. The color scheme represents Lewontin’s D’ values and logarithm of odds (LOD). LOD < 2 and D’ < 1 (white squares); LOD ≥ 2 and D’ < 1 (pink squares). The numbers within the squares refer to the Lewontin’s D’ × 100