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

Abstract

Introduction Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions including its catalytic activity towards producing extra-testicular androgen. The present study is towards understanding interaction between biological, lifestyle and genetic impacts of AKR1C3 and their influence on clinical factors in a prostate cancer (PC) cohort from New Zealand (NZ). Method Characteristics of 516 PC patients were collected from the Auckland Regional Urology Facility, NZ. These men were genotyped for the AKR1C3 rs12529 single nucleotide polymorphism (SNP). The leukocyte AKR1C3 activity was measured in a sub-cohort. Variability of leukocyte AKR1C3 activity between biological, lifestyle and clinical features as well as correlation between biological and clinical features were assessed with and without genetic stratification. Results The leukocyte AKR1C3 activity was associated with age at diagnosis (0.51 vs 0.34 μM coumberol units for >69y vs ≤69y, P = 0.03); and with anatomic stage/prognostic grouping among the AKR1C3 rs12529 CC genotype carriers (0.50 vs 28 μM coumberol units among low- and high-risk groups respectively, P = 0.02). Significant correlation between leukocyte AKR1C3 activity and age at PC diagnosis was also observed (correlation coefficient 0.20 and P = 0.02). Ever- smoking impacted both age and PSA at PC diagnosis among AKR1C3 rs12529 GG and CG genotype carriers respectively. Age at diagnosis significantly correlated with PSA at diagnosis in the main (correlation coefficient 0.29, and P<0.001) and sub-cohorts (correlation coefficient 0.24, and P = 0.01); and those carrying the AKR1C3 rs12529 CG and GG genotypes in both the main (correlation coefficient 0.30, and P<0.001 and correlation coefficient 0.35, and P<0.001 respectively) and sub-cohorts (correlation coefficient 0.43, and P<0.001 and correlation coefficient 0.39, and P = 0.06 respectively); but not with those carrying the CC genotype. Conclusions Age dependent PSA thresholds in PC screening could have been valid only in men carrying the AKR1C3 rs12529 CG and GG genotypes in this NZ cohort.

Assessment of Factors Associated with PSA Level in Prostate Cancer Cases and Controls from Three Geographical Regions.

“…AKR1C3 is known as an epithelial-mesenchymal transition driver in prostate cancer metastasis [46] . In a small group of men with prostate cancer from NZ, we have shown a signi cant increase in leukocyte AKR1C3 activity level with age at diagnosis, and upon genetic strati cation this shows a trend among cases carrying the AKR1C3 rs12529 GG genotype only [24] . Additionally, our previous study showed that men carrying the AKR1C3 rs12529 GG genotype carry higher levels of leukocyte AKR1C3 activity, if their PSA was > 20ng/ml, compared to those carrying a PSA level ≤ 20ng/ml.…”

“…Other AKR1C3 genetic polymorphisms have also been associated with benign prostate hyperplasia-related factors including dihydrotestosterone inactivation and prostate volume [23] . Meanwhile, our data suggests that the age-based PSA variation is restricted to the AKR1C3 rs12529 CG and GG genotype carriers in a New Zealand (NZ) prostate cancer cohort [24] . In that study, we also showed that ever-smoking in uenced both age and PSA at prostate cancer diagnosis among the AKR1C3 rs12529 GG and CG genotype carriers, respectively.…”

“…Details of the NZ prostate cancer patient cohort (N=515) considered in this analysis are described in detail elsewhere [24] .…”

“…This could result in increased DNA damage in tissue including that of the prostate glandular epithelium with subsequent increases in serum PSA levels. Our previous analysis showed that men carrying the AKR1C3 rs12529 GG genotype and are ever-smokers are diagnosed at a higher age compared to the same genotype carriers who are never-smokers; and men carrying the AKR1C3 rs12529 CG genotype and ever-smokers are diagnosed at a higher PSA level compared to the same genotype carriers who are never-smokers [24] . If the current tested cases and controls cohorts have su ciently represented the general NZ, US and TW men, the current ndings pose the question of validity of the age-based PSA thresholds to be used in prostate cancer screening of all US-EA men or the speci c AKR1C3 rs12529 genotype strati ed groups in NZ, US-AA, and TW men.…”

Selenium Supplementation and Prostate Health in a New Zealand Cohort

“…There was no overall significant correlation between the difference in serum selenium after supplementation and subsequent difference in PSA level, although significant correlations were recorded among, men below the median age of 55 years as well as the group who were never-smokers. Our previous studies have shown that age based PSA increase in men with prostate cancer beyond 69 years could be due to the increase in extra-testicular androgen production from adrenal dehydroepiandrosterone (DHEA)-based androgen precursors [65] catalyzed by the AKR1C3 enzyme, particularly among men carrying the AKR1C3 rs12529 CG and GG genotypes [66]. Therefore, our current observation of a significant inverse correlation between the difference in serum selenium and difference in PSA level after selenium supplementation among men below the age of 55 years may indicate that increased selenium level does not support a significant reduction in PSA when the extra-testicular androgen production starts to increase with advancing age.…”