Assessment of factors associated with PSA level in prostate cancer cases and controls from three geographical regions.

It is being debated whether prostate-specific antigen (PSA)-based screening effectively reduces prostate cancer mortality. Some of the uncertainty could be related to deficiencies in the age-based PSA cut-off thresholds used in screening. Current study considered 2779 men with prostate cancer and 1606 men without a cancer diagnosis, recruited for various studies in New Zealand, US, and Taiwan. Association of PSA with demographic, lifestyle, clinical characteristics (for cases), and the aldo-keto reductase 1C3 (AKR1C3) rs12529 genetic polymorphisms were analysed using multiple linear regression and univariate modelling. Pooled multivariable analysis of cases showed that PSA was significantly associated with demographic, lifestyle, and clinical data with an interaction between ethnicity and age further modifying the association. Pooled multivariable analysis of controls data also showed that demographic and lifestyle are significantly associated with PSA level. Independent case and control analyses indicated that factors associated with PSA were specific for each cohort. Univariate analyses showed a significant age and PSA correlation among all cases and controls except for the US-European cases while genetic stratification in cases showed variability of correlation. Data suggests that unique PSA cut-off thresholds factorized with demographics, lifestyle and genetics may be more appropriate for prostate cancer screening.

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

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.

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.

INTRODUCTION: The 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. METHOD: NZ 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. RESULTS: NZ 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. CONCLUSIONS: High-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.

Environmental factors and risk of aggressive prostate cancer among a population of New Zealand men - a genotypic approach.

Prostate cancer is one of the most significant health concerns for men worldwide. Numerous researchers carrying out molecular diagnostics have indicated that genetic interactions with biological and behavioral factors play an important role in the overall risk and prognosis of this disease. Single nucleotide polymorphisms (SNPs) are increasingly becoming strong biomarker candidates to identify susceptibility to prostate cancer. We carried out a gene × environment interaction analysis linked to aggressive and non-aggressive prostate cancer (PCa) with a number of SNPs. By using this method, we identified the susceptible alleles in a New Zealand population, and examined the interaction with environmental factors. We have identified a number of SNPs that have risk associations both with and without environmental interaction. The results indicate that certain SNPs are associated with disease vulnerability based on behavioral factors. The list of genes with SNPs identified as being associated with the risk of PCa in a New Zealand population is provided in the graphical abstract.

Quality of life effects of androgen deprivation therapy in a prostate cancer cohort in New Zealand: can we minimize effects using a stratification based on the aldo-keto reductase family 1, member C3 rs12529 gene polymorphism?

BACKGROUND: Androgen deprivation therapy (ADT) is an effective palliation treatment in men with advanced prostate cancer (PC). However, ADT has well documented side effects that could alter the patient's health-related quality of life (HRQoL). The current study aims to test whether a genetic stratification could provide better knowledge for optimising ADT options to minimize HRQoL effects. METHODS: A cohort of 206 PC survivors (75 treated with and 131 without ADT) was recruited with written consent to collect patient characteristics, clinical data and HRQoL data related to PC management. The primary outcomes were the percentage scores under each HRQoL subscale assessed using the European Organisation for Research and Treatment of Cancer Quality of Life questionnaires (QLQ-C30 and PR25) and the Depression Anxiety Stress Scales developed by the University of Melbourne, Australia. Genotyping of these men was carried out for the aldo-keto reductase family 1, member C3 (AKR1C3) rs12529 single nucleotide polymorphism (SNP). Analysis of HRQoL scores were carried out against ADT duration and in association with the AKR1C3 rs12529 SNP using the generalised linear model. P-values <0 · 05 were considered significant, and were further tested for restriction with Bonferroni correction. RESULTS: Increase in hormone treatment-related effects were recorded with long-term ADT compared to no ADT. The C and G allele frequencies of the AKR1C3rs12529 SNP were 53·4 % and 46·6 % respectively. Hormone treatment-related symptoms showed an increase with ADT when associated with the AKR1C3 rs12529 G allele. Meanwhile, decreasing trends on cancer-specific symptoms and increased sexual interest were recorded with no ADT when associated with the AKR1C3 rs12529 G allele and reverse trends with the C allele. As higher incidence of cancer-specific symptoms relate to cancer retention it is possible that associated with the C allele there could be higher incidence of unresolved cancers under no ADT options. CONCLUSIONS: If these findings can be reproduced in larger homogeneous cohorts, a genetic stratification based on the AKR1C3 rs12529 SNP, can minimize ADT-related HRQoL effects in PC patients. Our data additionally show that with this stratification it could also be possible to identify men needing ADT for better oncological advantage.

An examination of clinical differences between carriers and non-carriers of chromosome 8q24 risk alleles in a New Zealand Caucasian population with prostate cancer.

Background. Prostate cancer makes up approximately 15% of all cancers diagnosed in men in developed nations and approximately 4% of cases in developing nations. Although it is clear that prostate cancer has a genetic component and single nucleotide polymorphisms (SNPs) can contribute to prostate cancer risk, detecting associations is difficult in multi-factorial diseases, as environmental and lifestyle factors also play a role. In this study, specific clinical characteristics, environmental factors and genetic risk factors were assessed for interaction with prostate cancer. Methods. A total of 489 prostate cancer cases and 427 healthy controls were genotyped for SNPs found on chromosome 8q24 and a genetic risk score was calculated. In addition the SNPs were tested for an association with a number of clinical and environmental factors. Results. Age and tobacco use were positively associated, whilst alcohol consumption was negatively associated with prostate cancer risk. The following SNPs found on chromosome 8q24 were statistically significantly associated with prostate cancer: rs10086908, rs16901979; rs1447295and rs4242382. No association between Gleason score and smoking status, or between Gleason score and genotype were detected. Conclusion. A genetic risk score was calculated based on the 15 SNPs tested and found to be significantly associated with prostate cancer risk. Smoking significantly contributed to the risk of developing prostate cancer, and this risk was further increased by the presence of four SNPs in the 8q24 chromosomal region.

Prostate disease risk factors among a New Zealand cohort.

BACKGROUND: Prostate cancer is a leading public health burden worldwide, and in New Zealand it is the most commonly registered cancer and the third leading cause of cancer deaths among males. Genetic variability and its associations with diet, demographic and lifestyle factors could influence the risk of this disease. METHODS: The single nucleotide polymorphisms (SNPs) within a group of antioxidant genes and related markers were tested between patient and control cohorts, adjusted for significant differences between basic lifestyle and demographic characteristics. RESULTS: Increasing age, smoking and low serum selenium levels were significantly associated with an increased risk for prostate disease. Alcohol consumption increased the glutathione peroxidase (GPx) activity. A significant reduction in alcohol consumption was recorded with prostate disease. Three SNPs, namely GPx1 rs1050450, SEL15 rs5845 and CAT rs1001179, were significantly associated with prostate disease risk. A cumulative risk of prostate cancer was noted with 6 risk alleles. A lower GPx activity was recorded with prostate disease compared to the controls. However, the GPx1 rs1050450 allele T in association with prostate cancer recorded a significantly higher GPx activity compared to the controls. CONCLUSIONS: These data point to a possibility of identifying individuals at risk of prostate cancer for better management purposes.