Polygenic risk and germline genetics for prostate cancer in Asians: Where do we stand?

INTRODUCTION
Prostate cancer ranks as the second most common male cancer globally, with rising incidence in Asian countries over recent decades. In Taiwan, cases doubled from 2000 to 2017, with similar trends across China, Japan, and South Korea [123]. In Japan specifically, age-standardized incidence rose from approximately 15 per 100,000 in 2000 to 45.6 per 100,000 in 2018—a threefold increase over two decades—though still lower than Western countries [4]. These epidemiological shifts reflect complex interactions between environmental changes, improved detection, and underlying genetic susceptibilities that manifest differently across ethnicities.
Genetic factors account for approximately 42% of prostate cancer risk, making it among the most heritable cancers [5]. Two complementary genetic approaches have emerged: polygenic risk scores (PRS) aggregating common variants from genome-wide association studies, and germline testing for rare high-penetrance mutations in DNA damage repair and other cancer pathways [67]. The 2025 BARCODE1 trial published in the New England Journal of Medicine demonstrated that men in the top 10% of genetic risk showed 40.0% cancer detection with 55.1% clinically significant disease—71.8% of which would have been missed by conventional screening [8]. While these results highlight the importance of polygenic germline risk and tailored management opportunities in early detection, this UK study included only European participants, limiting its applicability in Asian populations.
The imperative for Asian-specific research stems from multiple factors. Allele frequencies for prostate cancer variants differ substantially between populations, with the 8q24 locus showing markedly different effects in East Asians versus Europeans [910]. Unique population-specific variants exist, such as HOXB13 G132E prevalent in Europeans but absent in Koreans [11]. A 2025 Million Veteran Program study conducted in the United States confirmed HOXB13 G84E confers 3.17-fold risk, but only 0.06% of Asians carry this variant compared to 0.37% of Europeans men, underscoring population-specific genetic architecture [12]. Linkage disequilibrium patterns differ between ancestries, affecting both discovery and risk score portability [13]. For germline mutations, BRCA2 frequencies and variant spectra vary across ethnicities, and recent Chinese whole-exome sequencing identified novel candidate genes not previously reported in any population [14].
The emergence of large-scale Asian biobanks provides unprecedented opportunities. The Taiwan Precision Medicine Initiative (TPMI) encompasses >500,000 Han Chinese participants in 2025, Biobank Japan contains genetic data on >200,000 individuals, and the Korea Biobank enrolled >170,000 [151617]. These resources enable population-specific discovery and validation at scales approaching European cohorts. However, translation faces unique challenges including limited genetic counseling workforce, inconsistent insurance coverage, cost-effectiveness uncertainties in resource-constrained settings, and cultural factors affecting cascade testing acceptance [1819].
This review synthesizes current evidence on PRS and germline genetics specifically for Asian prostate cancer, evaluating performance, identifying ethnic-specific features, reviewing clinical guidelines, assessing implementation barriers, and defining future research priorities in the context of recent developments.

POLYGENIC RISK SCORES IN ASIAN POPULATIONS

1. Trans-ancestry studies
Genome-wide association studies have identified over 200 prostate cancer susceptibility loci, collectively explaining approximately 33% of familial risk [20]. A PRS mathematically aggregates variant effects through weighted summation, with top decile individuals typically showing 4- to 6-fold increased risk versus population median [21].
The landmark 2021 trans-ancestry meta-analysis by Conti et al. [20] assembled 107,247 cases and 127,006 controls across multiple ancestries (Table 1). For East Asians (1,652 cases, 1,803 controls), men in the 90th–100th percentile demonstrated 4.47-fold increased risk (95% confidence interval [CI] 3.52–5.68) versus the 40th–60th percentile, with 26% absolute lifetime risk in the top decile. Combined with age, the model achieved area under curve (AUC) 0.836 (95% CI 0.832–0.840). Importantly, mean PRS was 0.73-fold lower in East Asians than Europeans, indicating population-specific baseline differences with implementation implications.
The PRACTICAL Consortium multi-ethnic study (46 single nucleotide polymorphisms [SNPs] in 80,491 men including 2,382 Asian ancestry) showed Asian men in the 98th percentile had hazard ratio 3.77 for any cancer and 4.14 for aggressive disease [22]. However, the Asian cohort comprised only 3% of participants, limiting statistical power for ethnicity-specific analyses.

2. Population-specific development in East Asia
Rigorous studies have been conducted in East Asian populations within their respective regions. In South Korea, an initial 5-SNP model achieved AUC 0.605, while a later optimized 4-SNP version reached AUC 0.637 (95% CI 0.582–0.692) [2324]. Korean men in the top 5% showed 3.71-fold increased risk for any prostate cancer. Notably, PRS enhanced biochemical recurrence prediction post-prostatectomy, improving AUC from 0.844 to 0.888 when added to clinical parameters [23], demonstrating PRS utility beyond screening and extending to treatment stratification decisions in Asian men.
TPMI in Taiwan, encompassing >500,000 Han Chinese participants, represents the largest Asian genetic biobank [15]. Hung et al. [25] analyzed 24,778 men (903 cases) using the 269-SNP trans-ethnic model, achieving AUC 0.685. Top quartile men showed 4.77-fold increased risk and were diagnosed 2.7 years earlier (66.8 years vs. 69.5 years, p=0.002), but did not predict tumor aggressiveness or treatment outcomes. A 24-SNP PRS derived from genome-wide association study (GWAS) data demonstrated strong predictive performance for prostate cancer in a Taiwanese population, achieving an AUC of 0.824 and stable accuracy on cross-validation [26]. Individuals in the highest PRS quartile had a markedly increased risk compared with those in the lowest quartile (odds ratio [OR] 34.37), and the model retained good discrimination in an independent external validation cohort (AUC 0.757). A separate 2025 publication reported population-specific PRS for Han Chinese developed using Taiwan Biobank data, demonstrating superior performance compared to Eurocentric models across multiple diseases including prostate cancer [27].
A recent comprehensive review of prostate cancer in China emphasized the rising incidence (95% increase from 1990 to 2019) and identified genomic profiling as a priority for personalized screening [28]. The authors noted that while PRS shows promise, implementation requires addressing cost-effectiveness concerns in a middle-income population context. Cost-effectiveness analysis using microsimulation modeling evaluated 56 prostate-specific antigen (PSA) screening strategies in China, finding that while all methods were able to improve overall quality-adjusted life year (QALY) in all scenarios, a one-time genotyping were able to allow two-thirds of the population to either postpone screening age or increase intervals while maintaining cost and survival [29], suggesting that integration of PRS into such algorithms could further optimize cost-effectiveness by stratifying screening intensity in real-world scenarios.
In Japan, Akamatsu et al. [30] developed a 16-SNP model (AUC 0.659) in 1,438 Japanese men, with validation in 9,575 additional participants, where high PRS men showed 42.4% versus 10.7% biopsy positivity rates. Takata et al. [31] using 82 SNPs found top 5% men were diagnosed 2.7 years earlier, though only 80% of “Asian-associated” SNPs replicated in Japanese-specific analysis, demonstrating intra-Asian heterogeneity with worse performance when non-associated SNPs were added.
A multi-biobank international collaboration across Taiwan Biobank, Biobank Japan, and UK Biobank demonstrated feasibility of cross-population discovery, identifying hundreds of novel loci for 36 quantitative traits [32]. This collaborative framework showcased the maturation of Asian genomic infrastructure and provides a template for prostate cancer-specific consortia. Utilizing >100,000 East Asian participants alongside European controls, this study identified population-specific variants that would be missed in single-ancestry analyses.

3. Genetically adjusted PSA and prostate biopsy
PSA levels themselves are heritable (30%–41%) and influenced by common variants. A 2023 multi-ancestry GWAS (n=95,768) identified 128 PSA-associated variants, with three reaching genome-wide significance specifically in East Asians (n=3,337) [33]. The developed PRS explained 9.6% of PSA variation in East Asian validation cohorts, suggesting potential to refine screening by accounting for genetic influences on baseline PSA. This approach could reduce false positives in men with genetically elevated PSA but low cancer risk, and false negatives in men with genetically suppressed PSA but elevated cancer risk.
Akamatsu et al. [34] previously evaluated clinical utility of germline genetic testing with PRS among men undergoing prostate biopsy, finding higher prevalence of pathogenic variants with enrichment in cancer-positive biopsies (2.3% vs. 1.3% in negative biopsy). Top 10% had 4-fold increased risk of cancer detection compared to those of average PRS, supporting consideration of germline testing at diagnosis rather than reserving for metastatic disease, though cost-effectiveness of this expanded indication requires formal evaluation in Asian healthcare systems.
The most recent BARCODE1 trial recruited 6,393 UK men aged 55–69 years for PRS calculation using 130 variants [8]. Men in the ≥90th percentile (745 individuals) underwent multiparametric magnetic resonance imaging (MRI) and biopsy regardless of PSA, and among 468 who completed screening, 187 (40.0%) had cancer, with 103 (55.1%) intermediate or higher risk by National Comprehensive Cancer Network (NCCN) 2024 criteria. Remarkably, 71.8% of significant cancers would have been missed by the conventional UK pathway requiring elevated PSA plus positive MRI, underscoring the potential advantages of PRS in early detection. However, translation of this result to Asian populations raises critical questions. Should the 90th percentile threshold be maintained (classifying different absolute PRS given lower Asian baseline), or adjusted for population-specific incidence? Would detection rates be similar given lower Asian baseline incidence? Asian men often present with more aggressive features [35]—would the proportion of significant disease be higher? In addition, the western standards of prebiopsy MRI and transperineal biopsy are not uniformly available across Asia. Cost-effectiveness thresholds further differ substantially between high-income and middle-income Asian countries, mandating Asian-specific prospective trials using population-calibrated PRS models.

4. Limitations of current PRS
Despite progress, critical limitations persist. Current models predict overall incidence but show minimal discrimination for clinically significant or aggressive disease—the most relevant endpoint [25]. Sample size disparities between Asian and European ancestry limit discovery power [20]. Also, an important caveat is that ‘Asian’ populations are genetically heterogeneous, and most current evidence derives from East Asian cohorts (Chinese, Japanese, Korean). Substantial genetic diversity exists across the continent: South Asians (Indian subcontinent) show distinct ancestry components and different allele frequency distributions compared to East Asians, while Southeast Asian populations (e.g., Thai, Vietnamese, Filipino, Indonesian) represent additional genetic admixture patterns. PRS models developed in East Asians may not generalize to South or Southeast Asian populations without recalibration, hence the need for multiregional Asian collaborations encompassing diverse genetic ancestries. Prospective randomized trials demonstrating that PRS-guided interventions improve outcomes are also entirely lacking in Asian populations, with near-absence of GWAS and germline studies from South and Southeast Asia (collectively over 2 billion people). Implementation barriers include limited direct-to-consumer genetic testing acceptance in some Asian cultures, regulatory uncertainty regarding clinical-grade PRS products, and inadequate infrastructure for results interpretation and cascade testing [36].

GERMLINE MUTATION LANDSCAPE
Pathogenic germline mutation in prostate cancer is perhaps more widely researched in Asia than PRS due to its penetrance and the availability of actionable mutations with poly(ADP-ribose) polymerase inhibitors (PARPi) [37]. The nominal study by Pritchard et al. [38] established that 11.8% of metastatic prostate cancer harbors germline DNA damage response (DDR) mutations with BRCA2 being most prevalent, but included only 2% Asian patients (Table 2). Recent Asian studies have filled this gap, with a Korean whole-genome sequencing study of 340 metastatic cases identified germline pathogenic variants in 8.8% overall, with BRCA2 most frequent at 4.41%—significantly elevated versus Korean controls (OR 11.37, p<0.001) [11]. A comprehensive genomic analysis of 87 Chinese patients with metastatic hormone-sensitive prostate cancer found BRCA2 mutations to be most frequent of homologous recombination repair (HRR) genes, detected in 9.6% and followed by CDK12, RAD51C, and PALB2 [39]. BRCA2 mutations consistently associate with earlier diagnosis and younger mortality in a multiethnic study including Asians of Chinese descent [40], validating BRCA2 as clinically actionable across ethnicities.
BRCA1 remains rare (0.2%–0.8%) in Asian cohorts [1141]. ATM mutations occur in 0.8%–1.5%, PALB2 in 0.8%–1.2%. CHEK2 shows striking ethnic disparity—common in Europeans (2%–3%) but rare in East Asians (<0.5%) [4243]. Overall HRR mutations occur in 6%–10% of Asian unselected cohorts and 10%–15% of metastatic disease, modestly lower than Caucasian frequencies [11]. A comprehensive review of HRR mutations in Chinese cohorts showed unique variant spectra compared to Europeans, necessitating ethnicity-specific variant databases for accurate interpretation [28].
Other key mutations include mismatch repair (MMR) and HOXB13 mutations. Overall, MMR deficiency itself is rare (<3%) but clinically relevant given immunotherapy responsiveness [41]. So et al. [44] identified a novel MSH2 variant (c.1160_1166delinsCATAA) in 0.8% of Korean patients, with pathogenic frequency two-fold higher in Chinese metastatic cancer compared to Caucasians (4.8% vs. 2.2%, p=0.006) [45]. HOXB13 exemplified variability in genetic architecture with different variants responsible in ethnic-specific cohorts. The European G84E variant (c.251G>A, p.Gly84Glu) occurs in 1%–2% of Northern European cases, conferring 3- to 4-fold risk, but is virtually absent in Asians [4647]. The Million Veteran Program study of 592,158 men in US confirmed G84E confers 3.17-fold risk (95% CI 2.90–3.46) for any prostate cancer, 2.99-fold risk for metastatic disease, and 2.63-fold risk for prostate cancer-specific death [12]. However, in this predominantly European descent cohort, only 0.06% of Asian participants carried this variant compared to 0.37% of Europeans.
Conversely, the Asian G132E variant (c.394G>A, p.Gly132Glu) occurs in 1.7% of Korean, 0.8%–1.2% of Japanese, and 0.5%–1.0% of Chinese cases, but is absent in Europeans [11]. Both variants affect the homeobox DNA-binding domain but at different positions, with potentially distinct functional consequences. The Million Veterans Program study found that G84E carriers show no increased risk of aggressive features beyond their elevated overall risk—disease in these men was not more aggressive than sporadic cases [12]. Whether G132E similarly affects overall incidence without influencing aggressiveness requires dedicated Asian cohort studies.
Further 12 novel non-DDR predisposition genes have been discovered in a Chinese cohort [14], which identified 29% and 25.1% deleterious mutations in 100 Hong Kong and 167 Shanghai patients respectively. While 3 novel non-DDR genes have been discovered, the clinical implication of these findings remain in question as further validation is lacking, and follow-up functional studies are required.

CLINICAL GUIDELINES AND IMPLEMENTATION IN ASIA
The 2022 Hong Kong Consensus on Genetic Testing represents the first comprehensive Asian-specific guideline [18]. The expert panel recommends universal germline testing for: (1) metastatic castration-resistant prostate cancer (mCRPC); (2) high-risk localized/locally advanced disease (cN1 or cT3–4 or Grade Group 4–5); (3) personal history of earlyonset cancer (<50 years); (4) family history (≥2 first-degree relatives with breast/ovarian/pancreatic/prostate cancer, OR ≥1 first-degree with cancer <50 years); (5) Ashkenazi Jewish ancestry; (6) known family mutation carriers. Recommendation in gene panels were generally same, including the same core DDR genes (BRCA1, BRCA2, ATM, PALB2) and MMR genes (MLH1, MSH2, MSH6, PMS2) for germline.
The NCCN guidelines recommend germline testing for all men with metastatic, high-risk, or family-history-positive prostate cancer [48]. The Hong Kong Consensus aligns conceptually but adapts to Asian contexts by explicitly excluding CHEK2 and HOXB13 to account for differences in the aforementioned differences in variant detection frequency. Another critical difference is implementation context. Western guidelines assume availability of genetic counselors, established laboratory standards, and insurance reimbursement—conditions not uniformly present in Asia [49]. The Hong Kong Consensus acknowledges the severe shortage of genetic counselors in most Asian countries and limitations in research in Asian-specific mutational frequency. Therefore, the panels pragmatically recommend utilizing existing cancer genetic clinics, developing telemedicine counseling capacity, and advocacy for insurance coverage as well as taking ethnic and region-specific factors into consideration while treating patients.
Despite these efforts, multiple barriers impede guideline translation. Germline genetic heterogeneity even among East Asian subgroups is yet to be adequately addressed. Allele frequencies for prostate cancer risk variants show geographic variation across Chinese, Japanese, and Korean populations [20]. As mentioned, HOXB13 founder variants differ substantially across East Asia [125051], and BRCA2 and other HRR gene mutation spectra also vary between Korean, Chinese, and Japanese cohorts [114344], limiting a pan-“Asian” implementation of clinical guidelines. Genetic counselor workforce is also severely limited, with very different stages of establishing genetic counseling by region and many depending on a small number of clinicians with genetics expertise whose roles and responsibilities vary widely and are often constrained [49]. Insurance coverage for germline testing varies widely—fully or mostly covered in Japan and South Korea, partially covered in Taiwan, and largely out-of-pocket in China and Southeast Asia. Cost remains prohibitive for many individuals, with commercial panels cost USD 500–USD 2,000 in Asia, representing substantial financial burden in middle-income countries. Cultural factors affect uptake, as stigma regarding hereditary cancer, concerns about genetic discrimination, and preference for family privacy may reduce cascade testing acceptance [19].
Variant of uncertain significance (VUS) burden is disproportionately high in Asian populations due to limited representation in reference databases. ClinVar and similar resources contain predominantly European variant data, resulting in >40% of Asian patients receiving VUS results compared to <20% in Europeans [5051]. This creates counseling challenges and may reduce clinical utility. Infrastructure disparities are pronounced—urban academic centers may have comprehensive capabilities, while rural/regional facilities lack both testing access and counseling expertise.
Economic evaluation of germline testing in Asian populations is limited and extremely difficult due to variable healthcare systems. For instance, cost-effectiveness of germline BRCA testing-guided olaparib treatment in mCRPC from Western perspectives found marginal cost-effectiveness at approximately AU$ 100,000 per QALY [52]. Extrapolating to Asia requires adjusting for lower treatment costs, different willingness-to-pay thresholds, and variable insurance models. Given that PARP inhibitors improve progressionfree survival by 3–6 months in BRCA-mutated mCRPC, the absolute benefit may justify testing costs—but formal Asian cost-effectiveness analyses are needed for prostate cancer, with only comparable Korean results published coming from an ovarian cancer cohort [53].
For PRS-guided screening in prostate cancer, no formal Asian cost-effectiveness data exist. The 2025 Chinese PSA screening cost-effectiveness study provides a foundation: annual PSA screening at beginning at age 45 resulted in USD 5,080 per QALY could be enhanced by PRS stratification to reduce screening burden in low-risk men while intensifying surveillance in high-risk individuals, improving to USD 5,880 per QALY [29]. Modeling studies projecting PRS implementation costs are urgently needed, beginning with locoregional analyses and further expansion into nationwide and ethnic-wide cohorts.

FUTURE DIRECTIONS AND RESEARCH PRIORITIES
The most critical priority is expanding GWAS sample sizes through coordinated multi-ethnic collaborations (Fig. 1). Emerging initiatives show promise: the Taiwan Biobank (>500,000 participants), Biobank Japan (>200,000), and Korea Biobank >170,000) collectively represent approximately 1,000,000 individuals of Asian ethnicity [151617]. Recent analyses across Taiwan Biobank and Biobank Japan demonstrate feasibility of cross-population discovery for quantitative traits [32]. Establishing formal consortia analogous to PRACTICAL or ELLIPSE in European populations would enable mega-analyses identifying population-specific variants, improving PRS portability, and characterizing intra-Asian diversity (East Asian vs. South Asian vs. Southeast Asian). Standardized phenotyping, harmonized genotyping platforms, and data-sharing agreements are prerequisites.
Specific collaborative initiatives should prioritize: (1) establishing an Asia-Pacific Prostate Cancer Genetics Consortium analogous to PRACTICAL, with formal data-sharing agreements and harmonized phenotyping; (2) creating reference variant databases specifically for Asian populations to reduce VUS burden; (3) developing standardized genetic counseling protocols adapted to Asian cultural contexts, addressing family privacy concerns and genetic discrimination fears [37]; and (4) implementing pilot PRS screening programs in defined geographic regions (e.g., specific prefectures in Japan, provinces in China) to generate real-world cost-effectiveness and implementation data. Further integration of additional data including machine learning approaches to combine multi-modal data (genomic, transcriptomic, proteomic, imaging) could offer potential to identify aggressive phenotypes. The collaborative efforts have the possibility of becoming a new platform to validate applicability of geneticrisk based models developed in the West [8] as well as codevelopment of trans-ancestry models. However, overcoming gaps in healthcare systems as well as legal or regulatory barriers can be painfully slow and expensive, presenting a multi-layered obstacle to realizing the full potential of global genomic data sharing for research and healthcare [54].
In addition, further research can be performed in specific clinical scenarios for Asian populations. In Asian men with PSA levels in the diagnostic gray zone (2–10 ng/mL), PRS has emerging clinical relevance for refining biopsy decisionmaking [83334]. Incorporation of PRS into PSA interpretation has been shown to reduce unnecessary biopsies without compromising detection of clinically significant prostate cancer in European cohorts [33]. Notably, early data from Japan suggest a similar benefit in East Asian populations, with PRS-associated improvements in biopsy positivity comparable in magnitude to those achieved by the addition of MRI [34]. Moreover, combined risk stratification using PRS with established biomarkers such as the Prostate Health Index improves diagnostic accuracy beyond conventional markers alone, with particular benefit in gray-zone PSA cases [55]. In addition, analogous to strategies used for BRCA mutation carriers or individuals with a positive family history, PRS may inform risk-adapted screening intervals, including earlier or more intensive screening for those at high genetic risk. Although prior studies from China have not demonstrated a clear benefit [29], further evaluation in other Asian healthcare systems, such as Korea or Japan, is warranted, as differences in cost structures and screening practices may modify the clinical utility of genetic risk stratification. In this context, PRS has the potential to serve as a valuable adjunct to PSA-based screening and biopsy selection strategies in Asian populations and merits further research.

CONCLUSIONS
Substantial progress has characterized the genetic landscape of Asian prostate cancer over the past five years, yet critical gaps persist. PRS has consistently demonstrated effective risk stratification in Asian men, with individuals in the highest risk strata exhibiting markedly increased disease risk and clear potential to refine screening strategies. Nevertheless, current PRS models lack validation in Asia and substantial ethnic disparity remain in genome-wide analyses. While the landmark BARCODE1 trial established the clinical feasibility of PRS-guided screening in European populations, direct translation to Asian settings will require population-calibrated thresholds and prospective validation. Similarly, while germline profiling reveals a rich mutation landscape in Asian cohorts with 25.1%–29% harboring deleterious variants, much remain to be discovered. Ethnic-specific variants like HOXB13 G132E in Koreans suggest an unmet need for population-tailored test panels. The 2022 Hong Kong Consensus provides comprehensive Asian-specific testing guidelines, though implementation faces formidable barriers including limited genetic counseling workforce, inconsistent insurance coverage, high VUS burden, and infrastructure disparities.
Future priorities are clear: large-scale multi-ethnic collaborations leveraging emerging Asian biobanks must expand GWAS sample sizes toward parity with European studies. Prospective validation trials establishing clinical utility and cost-effectiveness of PRS-guided screening and germline-directed therapies in Asian contexts are urgently needed. Development of aggressive disease predictors integrating genomic and multi-omic data could transform clinical utility. Equitable implementation infrastructure addressing workforce, insurance, and technology gaps is essential to translate discoveries into improved outcomes.
The next decade offers unprecedented opportunity to achieve precision prostate cancer management for Asian men. Realizing this vision requires sustained investment in research infrastructure, clinical trial capacity, workforce development, and health equity initiatives. With coordinated action, the promise of personalized genetic medicine can extend beyond European populations to benefit the billions of men in Asia.