Association of SNPs in the PAI1 Gene with Disease Recurrence and Clinical Outcome in Bladder Cancer

SIMPLE SUMMARY: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. Previous studies have demonstrated that plasminogen activator inhibitor-1 (PAI1) plays an important role in bladder cancer development. The aim of our retrospective study was to assess the effects of PAI1 mutational status in bladder tumors. In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. We identified two clinically relevant 3′ untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1. Caucasian patients with at least one of the SNPs had a high risk of recurrence and shorter survival. Additional studies using cell lines demonstrated that one SNP increased the anti-apoptotic effect of PAI1, and another lost the control of cancer cellular growth. This study underscores the relevance and influence of these SNPs in bladder cancer. ABSTRACT: Purpose: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined. Methods: In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. Results: Sequencing analyses identified two clinically relevant 3′ untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type. Conclusion: Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.