Abstract:
Single nucleotide polymorphisms (SNPs) not only have the potential to be used as diagnostic markers for prostate cancer but can also be used as prognostic markers for advanced stages of prostate cancer as well as predicting patient response to androgen deprivation therapy (ADT). KPCI over-expression has been linked with prostate cancer and it has shown to promote malignancy by enhancing tumor cell motility and invasion. The aim of this study was to identify the association of KPCI missense variations rs1197750201 and rs1199520604 with prostate cancer and evaluate their potential as prognostic markers. KPCI activity, particularly in maintaining apical polarity, is controlled by its interactions with binding proteins such as Par-6. The effects of non-synonymous SNPs on KPCI molecular interactions with Par-6 were studied to understand downstream effects on KPCI pathways. Genotypic association of KPCI SNPs with PCa was determined through tetra-ARMS PCR while MD simulations of KPCI docked with Par-6, were performed to determine the effect on protein interactions. In silico analysis elucidated the negative impact of KPCI SNPs rs1199520604 (G34W) and rs1197750201 (F66Y) present in the PB1 domain of the regulatory region, on its structure and function. KPCI homozygous genotype TT has shown association with increased risk of PCa (p value=0.0006, OR=4.362, RR=2.093) and may be used as a prognostic marker. The identification of novel prognostic markers for prostate cancer will enable physicians to better predict treatment response leading to better therapeutic outcomes and lowered cases of therapy resistance.
