Influence of lifestyle and genetic variants in the aldo-keto reductase 1C3 rs12529 polymorphism in high-risk prostate cancer detection variability assessed between US and New Zealand cohorts

Abstract

IntroductionThe prostate-specific antigen (PSA) based prostate cancer (PC) screening is currently being debated. The current assessment is to understand the variability of detecting high-risk PC in a NZ cohort in comparison to a US cohort with better PSA screening facilities. Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions with a potential to regulate subsequent PSA levels. Therefore, we wish to understand the influence of tobacco smoking and the AKR1C3 rs12529 gene polymorphism in this variability.MethodNZ cohort (n = 376) consisted of 94% Caucasians while the US cohort consisted of African Americans (AA), n = 202, and European Americans (EA), n = 232. PSA level, PC grade and stage at diagnosis were collected from hospital databases for assigning high-risk PC status. Tobacco smoking status and the AKR1C3 rs12529 SNP genotype were considered as confounding variables. Variation of the cumulative % high-risk PC (outcome variable) with increasing PSA intervals (exposure factor) was compared between the cohorts using the Kolmogorov-Smirnov test. Comparisons were carried out with and without stratifications made using confounding variables.ResultsNZ cohort has been diagnosed at a significantly higher mean age (66.67± (8.08) y) compared to both AA (62.65±8.17y) and EA (64.83+8.56y); median PSA (NZ 8.90ng/ml compared to AA 6.86ng/ml and EA 5.80ng/ml); and Gleason sum (NZ (7) compared EA (6)) (p<0.05). The cumulative % high-risk PC detection shows NZ cohort with a significantly lower diagnosis rates at PSA levels between >6 - <10ng/ml compared to both US groups (p<0.05). These were further compounded significantly by smoking status and genetics.ConclusionsHigh-risk PCs recorded at higher PSA levels in NZ could be due to factors including lower levels of PSA screening and subsequent specialist referrals for biopsies. These consequences could be pronounced among NZ ever smokers carrying the AKR1C3 rs12529 G alleles making them a group that requires increased PSA screening attention.

Interaction between leukocyte aldo-keto reductase 1C3 activity, genotypes, biological, lifestyle and clinical features in a prostate cancer cohort from New Zealand

“…The frequencies between the AKR1C3 rs12529 genotypes are similar to that of the European Americans and African Americans recorded before [20, 28]. The frequency of the AKR1C3 rs12529 G allele in our cohort was 0.463 which is marginally lower than the frequencies recorded in the Genome Aggregation Database (0.499); but similar to the Trans-Omics for Precision Medicine Database (0.476); and higher than the TWINSUK Database (0.385) and Avon Longitudinal Study of parents and Children Database from the University of Bristol (0.382) (https://www.ncbi.nlm.nih.gov/snp/rs12529).…”

“…It is possible that PC patients carrying the AKR1C3 rs12529 G alleles have a higher impact of tobacco smoking affecting their PSA based PC diagnosis. We have previously recorded delayed diagnosis of high-risk PC in ever-smokers from NZ carrying the AKR1C3 rs12529 G allele when compared to similar cohorts from the US [20]. Elimination of those with the AKR1C3 rs12529 G allele for screen detected PC due to their lower PSA levels is a possibility with a subsequent delayed diagnosis with high-risk PC.…”

“…If this fact cannot be proven in larger cohorts elsewhere, it could be a NZ specific factor/s. We have previously recorded that our NZ PC cohort were diagnosed at higher age and PSA levels compared to that of African and Caucasian PC cohorts from US [20]. NZ has very specific conditions that might especially impact ever-smokers, including the relatively lower levels of available dietary selenium (Se) when compared to most other regions in the world.…”

“…Subsequently, patients were further stratified based on the disease stage/prognostic grouping followed the criteria defined by the 7 th edition of the American Joint Committee on Cancer (AJCC) abbreviated as I, IIA,IIB,III and IV as mentioned previously [20]. D’Amico et al retrospectively monitored a PC patient cohort that had undergone RP, and radiation implant with or without neoadjuvant ADT towards an outcome measure of PSA failure [23].…”

“…It is reported that the TMPRSS2-ERG fusion protein, which is well known for its expression in 70% of PCs [19], drives AKR1C3 expression by binding to the AKR1C3 gene promoter region in PC cell cultures [10]. Our recent comparison of high-risk PC diagnosis pattern between US and NZ cohorts has shown a disparity between the two centres, especially among men with an ever-tobacco smoking lifestyle and carrying one or two G alleles on the AKR1C3 rs12529 polymorphism [20]. We are of the view that delayed diagnosis of high-risk PC among NZ ever-smokers carrying the AKR1C3 rs12529 G allele is due to its association with lower PSA levels compounded by lower PSA screening in NZ.…”