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

• Published in: International journal of molecular sciences 2023-03, Vol.24 (5), p.4943
• Main Authors: Murakami, Kaoru, Furuya, Hideki, Hokutan, Kanani, Goodison, Steve, Pagano, Ian, Chen, Runpu, Shen, Cheng-Huang, Chan, Michael W Y, Ng, Chi Fai, Kobayashi, Takashi, Ogawa, Osamu, Miyake, Makito, Thornquist, Mark, Shimizu, Yoshiko, Hayashi, Kazukuni, Wang, Zhangwei, Yu, Herbert, Rosser, Charles J
• Format: Article
• Language: English
• Subjects: Apoptosis; Biomarkers; Bladder cancer; Cancer; Chromosomes; Clinical outcomes; Contact inhibition; Development and progression; Diseases; Evaluation; Genetic aspects; Haplotypes; Humans; Medical prognosis; Mutation; Neoplasm Recurrence, Local; Nucleotides; Oncology, Experimental; Patient outcomes; Patients; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen activator inhibitors; Polymorphism, Single Nucleotide; Relapse; Sequences; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Survival; Tumors; Urinary Bladder Neoplasms - genetics; White people
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24054943

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 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of in human bladder tumors has not been well defined. In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. Sequencing analyses identified two clinically relevant 3' untranslated region (UTR) single nucleotide polymorphisms (SNPs) in (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 ( = 0.03 and = 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. Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.