Abstract
The genes that influence prostate cancer progression remain largely unknown. Since the carboxylesterase gene family plays a crucial role in xenobiotic metabolism and lipid/cholesterol homeostasis, we hypothesize that genetic variants in carboxylesterase genes may influence clinical outcomes for prostate cancer patients. A total of 478 (36 genotyped and 442 imputed) single nucleotide polymorphisms (SNPs) in five genes of the carboxylesterase family were assessed in terms of their associations with biochemical recurrence (BCR)-free survival in 643 Taiwanese patients with prostate cancer who underwent radical prostatectomy. The strongest association signal was shown in CES1 (P = 9.64 × 10−4 for genotyped SNP rs8192935 and P = 8.96 × 10−5 for imputed SNP rs8192950). After multiple test correction and adjustment for clinical covariates, CES1 rs8192935 (P = 9.67 × 10−4) and rs8192950 (P = 9.34 × 10−5) remained significant. These SNPs were correlated with CES1 expression levels, which in turn were associated with prostate cancer aggressiveness. Furthermore, our meta-analysis, including eight studies, indicated that a high CES1 expression predicted better outcomes among prostate cancer patients (hazard ratio 0.82, 95% confidence interval 0.70–0.97, P = 0.02). In conclusion, our findings suggest that CES1 rs8192935 and rs8192950 are associated with BCR and that CES1 plays a tumor suppressive role in prostate cancer.
Highlights
Prostate cancer is the most commonly diagnosed cancer and the second most common cause of death among men, with an estimated 191,930 new cases and 33,330 deaths expected worldwide in 2020 [1]
Univariate Cox regression indicated that prostate-specific antigen (PSA), Gleason score, stage, and surgical margin were significantly associated with Biochemical recurrence (BCR) (P < 0.001)
Three single nucleotide polymorphism (SNP) were found to be associated with BCR (P < 0.05, Table S1), of which CES1 rs8192935 remained noteworthy after multiple test correction (q = 0.036)
Summary
Prostate cancer is the most commonly diagnosed cancer and the second most common cause of death among men, with an estimated 191,930 new cases and 33,330 deaths expected worldwide in 2020 [1]. Prognosis remains heterogeneous, suggesting that genetic factors may contribute to treatment response. Genome-wide association studies (GWASs) have successfully identified more than 100 prostate cancer susceptibility loci to date [2,3]. Further functional studies indicate that these risk loci are often located near genes, and regulate genes involved in carcinogenesis, including cell metabolism (JAZF1 and HNF1B) and DNA repair or cell cycle machinery (MYC, TERT, ATM, and CDKN1B) [4]. A pathway-based analysis using known prostate cancer susceptibility loci highlights the antigen presentation pathway and gene network of lipid metabolism, molecular transport, and small molecule biochemistry, which may contribute to prostate cancer development [5]
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