Abstract
Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1–10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.
Highlights
Prostate cancer (PC) is the most frequent non-cutaneous malignancy in the Western countries [1], and its incidence has been rapidly increasing in Asian countries including Japan [2]
Five novel variants we have identified in the Japanese genome-wide association studies (GWAS) [20] were included, and the total of 16 variants were incorporated into a genetic risk prediction model for PC as explanatory variables in a logistic regression model (Table 1).No variants were within the same linkage disequilibrium block, and all the variants selected were not correlated with (r2,0.2) each other
Reproducibility and discriminatory potential of the genetic risk prediction model The regression coefficients of the risk prediction model were positive for all the 16 variants except rs620861, indicating that the risk alleles of the variants selected based on stage1 of our GWAS are positive risk factors in AKY samples except at rs620861 (Table 1). rs620861 is in the so-called Block 3 of 8q24, and was first reported as a PC-susceptibility locus in a GWAS of European ancestry, and was confirmed to be associated with PC in stage 1 of our GWAS of the Japanese
Summary
Prostate cancer (PC) is the most frequent non-cutaneous malignancy in the Western countries [1], and its incidence has been rapidly increasing in Asian countries including Japan [2]. Novel biomarkers that can risk stratify patients at gray-zone PSA to decide who should be recommended to undergo prostate biopsies are urgently needed. We have previously identified five novel loci associated with PC in the GWAS of Japanese, and reported that 19 of the 31 reported loci were replicated (P-value,0.05) in the Japanese, 12 were not, confirming the presence of ethnic heterogeneity in genetic susceptibility to PC [20]. Some of the five novel loci we have identified were later replicated in a Caucasian population at lower odds ratios and some were not [23,24] These data suggest that genetic risk prediction models should be individualized to each ethnic group.
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