Date Published: May 24, 2019
Publisher: Public Library of Science
Author(s): Nishi Karunasinghe, Eva Symes, Amy Gamage, Alice Wang, Pam Murray, Shuotun Zhu, Megan Goudie, Jonathan Masters, Lynnette R. Ferguson, Chih-Pin Chuu.
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).
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.
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. 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.
Prostate Cancer (PC) is the most common non-skin cancer among men in developed countries [1, 2]. In New Zealand (NZ) there were 3199 PC registrations and 607 PC-related deaths in 2012. The status of PC risk varies between individuals in terms of the patient’s lifestyle and biological characteristics [4–6]. For PC management purposes, it is important to differentiate between men carrying indolent cancers from those with high-risk cancers. Routine assessments for PC include the digital rectal examination and the serum prostate-specific antigen (PSA) blood test, and a subsequent biopsy to confirm diagnoses. However, PC screening with PSA is currently debated due to its low specificity . According to Merriel et al 2018 evaluations on performance of the PSA-based screening for diagnosis of both asymptomatic and symptomatic PC stands equivocal . There are no specific serum PSA levels that are defined as normal/abnormal for men in any racial or ethnic group .
This study presents an analysis of interaction between AKR1C3 activity, AKR1C3 rs12529 genotypes, biological and clinical features in a PC cohort from Auckland, NZ. The leukocyte AKR1C3 activity was measured only in a sub-cohort. Due to the sub-cohort showing significantly higher age and PSA at PC diagnosis as well as a higher PC severity as shown by Gleason sum data, the former is not entirely representing the main cohort. The sub-cohort and those with the AKR1C3 rs12529 CC and CG genotypes within the sub-cohort showed a negative correlation of BMI with age at PC diagnosis, although this was not seen in the main cohort except for a marginal negative trend shown among those carrying the AKR1C3 rs12529 CC genotype in the main cohort. As age dependent BMI change is not directly relevant to the theme of this manuscript, it is considered towards the end of the discussion.