IntroductionPolygenic risk scores (PRS) offer a novel means of stratifying breast cancer risk, with the potential to personalize screening protocols and measures, and thus improve early detection. However, their implementation in real-world settings remains poorly understood. This study, as part of the BRIGHT project, investigates how PRS-based breast cancer screening is being piloted, adapted, and resisted across five European countries, Estonia, Portugal, Spain, Sweden, and France, drawing on a combination of implementation science and business model theory.MethodsWe employed a multiple-case study approach, conducting 94 semi-structured interviews with stakeholders across healthcare, policy, industry, and civil society. Analysis was guided by the Value-Information-Process (VIP) framework and complemented by selected constructs from the Consolidated Framework for Implementation Research (CFIR). Data were coded thematically and triangulated with national policy documents, pilot evaluations, and stakeholder workshops.ResultsImplementation trajectories varied significantly across contexts. Estonia demonstrated advanced policy-driven integration enabled by digital infrastructure and centralized governance. Sweden and Spain followed pilot-to-policy models, with strong regional autonomy but slower national uptake. Portugal exhibited market-led adoption driven by private sector innovation, while France pursued a trial-first logic centered on MyPeBS. Common barriers included limited clinical guidelines, low genetic literacy among frontline providers, fragmented IT systems, and slow and unclear Health Technology Assessment (HTA) cycles. Key facilitators included strong institutional alignment, biobank-linked infrastructures, and public trust in preventive care.DiscussionSuccessful PRS implementation requires more than scientific validation; it depends on systemic readiness across value narratives, information systems, and governance processes. PRS-based screening thus serves as a test case for the broader challenge of integrating personalized genomics into public health. Findings offer strategic guidance for policymakers, clinicians, and researchers designing future-ready prevention pathways.

Germline genetic testing (GT) of cancer-associated genes enables the identification of hereditary risk in breast (BC) and ovarian cancer (OC) patients, supporting early diagnosis and personalized treatment strategies. In this study, we analyzed data from 3,537 patients who underwent routine clinical GT in Estonia between 2007–2023, including 2,856 BC and 759 cases of OC. A total of 78 individuals in the study were diagnosed with both BC and OC. The mean age at diagnosis and GT was 50.4 ± 12.0 and 54.0 ± 12.5 years for BC, and 56.1 ± 14.1 and 59.4 ± 13.3 years for OC, respectively. Non-genetic medical specialists ordered most GT (66.1%). GT increased nine-fold over the course of the study period. Altogether, 687 pathogenic/likely pathogenic variants (PV) were identified in 668 individuals (17.4% in BC, 26.0% in OC), with an overall combined PV detection rate of 18.9%. The most frequently mutated genes were BRCA1 (6.9% BC; 16.3% OC), BRCA2 (3.8%; 4.5%), and CHEK2 (3.5%; 1.7%). Two BRCA1 PV, c.5266dup and c.4035del, accounted for 29.1% of all PV detected. In addition to BRCA1/2, we identified 19 non-BRCA cancer susceptibility genes in 243 individuals and 25 novel PV, which demonstrates the importance of multi-gene NGS-based GT in Estonia for identifying hereditary cancer risk.

Abstract Background Type I hereditary hemochromatosis (HH), caused by pathogenic HFE variants, is among the most common autosomal recessive disorders in Northern Europe. HH genotype–phenotype associations have been difficult to predict due to variable variant penetrance and expressivity. In this study, population-based biobank data were used to conduct a large-scale analysis of symptoms associated with different HH genotypes and their potential genetic modifiers. Methods Linked genotypic and electronic health records from the Estonian Biobank (n = 211,994) and UK Biobank (n = 405,931) were used to investigate HH genotype–phenotype associations. Pathogenic variants of all HH types in the Estonian Biobank sample were identified. Clinical markers derived from laboratory measurements and diagnosis codes were compared between HFE pathogenic variant carriers and controls [chi-squared test, phenome-wide association study (PheWAS)]. Carrier subgroups were defined according to the presence of p.C282Y, p.H63D, p.S65C, and all pairwise combination genotypes. Kruskal–Wallis and Mann–Whitney U tests were used to identify ICD-10 codes and genotype groups with significantly different mean ages at first diagnosis. Genome-wide association studies (GWAS) based on ceruloplasmin and ferritin concentrations were conducted to identify potential genetic modifiers. Fine-mapping was used to identify putatively causal single nucleotide polymorphisms (credible sets) in the Estonian Biobank GWAS results. Fixed-effects meta-analyses of combined GWAS results from both biobanks were performed. Results We conducted the largest PheWAS with data from HFE variant carriers to date and catalogued pathogenic HH variants in the Estonian population. p.S65C homozygotes and p.C282Y/p.S65C heterozygotes in the Estonian Biobank sample were diagnosed with urogenital conditions (ICD-10 codes N42 and N50.8) at significantly higher rates than were controls. On average, N42 was first diagnosed 11 years earlier in p.S65C compound heterozygotes and homozygotes than in controls. We also identified a novel GWAS hit, CP rs61733458, with a significant impact on the ceruloplasmin level and ties to iron metabolism–related diseases. Conclusions Our results suggest that the p.S65C variant is more clinically relevant than previously thought and should be integrated more into HH testing guidelines. CP variant rs61733458 is a potential genetic modifier associated with iron metabolism–related diseases.

OBJECTIVE:To explore women's experiences following polygenic risk score (PRS) testing for breast cancer risk and to assess the knowledge, attitudes, practices (KAP), and implementation perspectives of medical professionals and healthcare decision-makers in Sweden. METHODS:Convergent mixed-methods study combining quantitative survey data with qualitative thematic analysis of survey open-ended responses and focus group discussion (FGD) notes. SETTING:Swedish healthcare context. PARTICIPANTS:400 women receiving PRS results for a first Participants Feedback Survey; 289 women for the second Participants Feedback Survey, and 6 medical professionals/decision-makers for a KAP survey and FGD. Women completed two sequential online feedback surveys post-PRS result disclosure. Professionals completed a KAP survey and participated in an FGD. Quantitative survey data were analysed using descriptive statistics. Qualitative data from open-ended survey questions and FGD notes were analysed using thematic analysis. RESULTS:Participants valued participation in PRS testing and receiving PRS-test results, with 87% finding results interesting and 82% finding them valuable. Although most participants found the explanations understandable (approximately 75% in Survey 1 and 82% in Survey 2), qualitative comments indicated that some had difficulty interpreting probabilistic risk information, including participants who self-identified as highly educated or medically trained. Negative emotional impact was generally minimal (85% felt calm), though some women with high PRS risk experienced anxiety. Major unmet needs included clearer explanations, actionable guidance, and better access to follow-up support from healthcare. Professionals were cautiously positive: in the KAP survey, 5 of 6 were familiar with the concept of PRS, but confidence in the health system's readiness to integrate it was limited. The main barriers raised were the absence of clinical guidelines and the need for evidence of clinical utility. CONCLUSIONS:Breast cancer PRS testing holds potential for enhancing risk assessment in Sweden. Key challenges for clinical integration include clinician readiness, the development of clear guidelines, and improved participant comprehension and communication. PRS tests should be accompanied with clinical decision support both for patients as well for medical professionals. Addressing these will require person-centered communication tools, robust evidence of clinical utility, well-defined clinical pathways, investments in provider education, and equitable implementation strategies within the Swedish healthcare system. CLINICAL TRIAL NUMBER:Not applicable.

BackgroundGenetic testing for likely pathogenic/pathogenic variants (PV) in BRCA1, BRCA2, and other cancer-associated genes plays a critical role in the diagnosis, prognosis, and management of breast and ovarian cancer (BCOC). Extending testing to healthy family members (HFM) of affected individuals enables early prevention strategies and timely referrals for enhanced screening, thereby improving cancer risk management. This study aimed to characterize the demographic profile and genetic findings among HFMs of BCOC patients in Estonia within routine clinical practice.MethodsA retrospective analysis was conducted on 3,472 HFMs who underwent genetic testing. Demographic data were collected, and the presence of PVs was assessed. Statistical comparisons were made between individuals with and without known familial PVs, and between male and female participants, using descriptive statistics and proportion comparisons.ResultsOf the 3,472 HFMs tested, 87.6% were female and 12.4% male, with a mean age of 41.1 ± 13.0 years. Notably, 78.6% were younger than 51 years, the typical age for initiating standard screening. PVs were identified in 683 individuals (19.7%). Among those with a known familial PV (n = 1,009), 41.8% were carriers, compared to 8.0% among those without a known familial PV (n = 2,408). Males were more likely to be tested when a familial PV was known (26.6%) than when it was not (6.6%), and 34.0% of tested males were PV carriers. PVs were found in 23 different genes, with BRCA1/2 accounting for 58.4% of all PVs, followed by ATM, BRIP1, CHEK2, and PALB2.ConclusionThe findings highlight the value of genetic testing in identifying at-risk individuals among HFMs of BCOC patients. The predominance of BRCA1/2 variants and the significant detection rate among younger individuals underscore the importance of early testing. The expansion of HFM testing in Estonia reflects increased public awareness and clinical integration of genetic risk assessment in cancer prevention strategies.

BACKGROUND:Breast cancer (BC) remains the most common type of cancer and the leading cause of cancer-related deaths in women despite the widespread screening programs and personalized treatment options. Current age-based screening programs are suboptimal missing high-risk young women. The "Be RIGHT with breast cancer risk management" (BRIGHT) study evaluated a genetic risk-based personalized BC screening service model in real-world healthcare settings, focusing on younger women excluded from standard screening. METHODS:The BRIGHT study included 800 healthy Estonian women aged 35 to 49 using telemedicine and home-based testing. Participants underwent polygenic risk score (PRS) testing and based on the questionnaire those meeting the monogenic pathogenic variant (MPV) testing criteria were referred to clinical geneticists. All women received personalized genetic risk-based clinical recommendations, and if needed, referral to BC screening. Participants' and healthcare professionals' feedback was collected. RESULTS:330 (41.3%) women with elevated polygenic risk received recommendations to start screening earlier than the current standard. 124 (15.5%) women were advised to begin BC screening immediately, among whom one was diagnosed with stage 0 cancer and one with a precancerous lesion. Of the 90 participants completing MPV testing, four (4.4%) were MPV-positive. Feedback indicated high satisfaction with the digital approach and a clear understanding of results and recommendations. CONCLUSIONS:The study demonstrated the feasibility and acceptability of a personalized genetic risk-based BC screening model. It has the potential to enhance BC screening programs, particularly for younger women and those at higher genetic risk, while avoiding unnecessary interventions for low-risk individuals.

Large biobanks have set a new standard for research and innovation in human genomics and implementation of personalized medicine. The Estonian Biobank was founded a quarter of a century ago, and its biological specimens, clinical, health, omics, and lifestyle data have been included in over 800 publications to date. What makes the biobank unique internationally is its translational focus, with active efforts to conduct clinical studies based on genetic findings, and to explore the effects of return of results on participants. In this review, we provide an overview of the Estonian Biobank, highlight its strengths for studying the effects of genetic variation and quantitative phenotypes on health-related traits, development of methods and frameworks for bringing genomics into the clinic, and its role as a driving force for implementing personalized medicine on a national level and beyond.

Background/Objectives: Polygenic risk scores (PRSs) have been extensively studied and are increasingly applied in healthcare. One of the most studied and developed areas is predictive medicine for breast cancer, but there is no wider consensus on the indications for the clinical use of PRSs for breast cancer. This current guidance endeavours to articulate the scientific evidence underpinning the clinical utility of PRSs in stratifying breast cancer risk, with a particular emphasis on clinical application. Methods: This guidance has been prepared by a group of experts who have been active in breast cancer PRS research and development, combining a review of the evidence base with expert opinion for indications for clinical use. Results: Based on data from various studies and existing breast cancer prevention and screening services, the indications for clinical use of breast cancer PRSs can be divided into the following scenarios: (1) Management of cancer-free women with a family history of cancer; (2) individual personalised breast cancer prevention and screening in healthcare services; and (3) breast cancer screening programs for more personalised screening. Conclusions: The integration of PRSs into clinical practice enables healthcare providers to deliver more accurate risk assessments, personalised prevention strategies, and optimised screening programmes, thereby improving patient outcomes and enhancing the effectiveness of breast cancer care. PRS testing represents a novel component in clinical breast cancer risk assessment, supporting a personalised, risk-based approach to breast cancer prevention and screening.

Population-based biobanks enable genomic screening to support initiatives that prevent disease onset or slow its progression and to estimate the prevalence of genetic diseases in the population. Wilson’s disease (WD) is a rare genetic copper-accumulation disorder for which timely intervention is crucial, as treatment is readily available. We studied WD in the Estonian Biobank population to advance patient screening, swift diagnosis, and subsequent treatment. Combined analysis of genotype and phenotype data from electronic health records (EHRs) consolidated at the Estonian biobank led to the identification of 17 individuals at high risk of developing WD, who were recalled for further examination and deep phenotyping. All recall study participants, regardless of phenotype, age, and prior WD diagnosis, had low serum ceruloplasmin and copper levels, and 87% also exhibited signs of early to late neurodegeneration. The p.His1069Gln variant in ATP7B, a prevalent pathogenic mutation, showed a striking four- to five-fold enrichment in Estonians compared with other populations. Based on our analysis of genetic and nationwide health registry data, we estimate that WD remains underdiagnosed and undertreated in Estonia. Our study demonstrates that personalized medicine, implemented with the collaboration of medical professionals, has the potential to reduce the healthcare burden by facilitating the accurate diagnosis of rare genetic diseases. To our knowledge, this report is the first to describe a large-scale national biobank–based study of WD.

BACKGROUND:Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Temporomandibular joint (TMJ) is among the most commonly affected joints in JIA patients. When JIA involves the TMJ, it may affect condylar growth in the joint; therefore, JIA patients are at risk of unfavourable long-term outcomes from associated joint damage. If undetected, TMJ involvement can lead to various functional disabilities such as reduced mandibular mobility and disorders of the mastication muscles. Limitations in sagittal and vertical mandibular growth can result in micrognathia and anterior open bite with aesthetic and functional restrictions. OBJECTIVE:Genetic factors may play a role in determining which individuals are more prone to develop TMJ disorders or in predicting the severity of the disease process. Therefore, we applied a GWAS approach to identify loci associated with TMJ involvement in a sample of Estonian patients with JIA. Our aim was to address the potential role of genetic susceptibility factors in TMJ-JIA, a condition not previously studied in this context. METHODS:The case group consisted of 55 JIA patients with TMJ involvement and 208 patients without TMJ involvement comprised the control group. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. Imputation was performed using a nationwide reference panel obtained of 2240 individuals whose data were obtained from the Estonian Biobank. RESULTS:We identified six loci as being associated with the risk of TMJ-JIA in Estonian JIA patients. The strongest associations were identified at CD6 rs3019551 (P = 3.80 × 10-6), SLC26A8/MAPK14 rs9470191 (P = 6.15 × 10-6), NLRP3 rs2056795 (P = 8.91 × 10-6) and MAP2K4 rs7225328 (P = 1.64 × 10-5). CONCLUSION:This study provides first insights into the risk-associated loci between JIA and its manifestation in the TMJ. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that render the TMJ susceptible to involvement by JIA in Estonian patients.

AbstractLarge biobanks have set a new standard for research and innovation in human genomics and implementation of personalised medicine. The Estonian Biobank was founded a quarter of a century ago, and its biological specimens, clinical, health, omics, and lifestyle data have been included in over 800 publications to date. What makes the biobank unique internationally is its translational focus, with active efforts to conduct clinical studies based on genetic findings, and to explore the effects of return of results on participants. In this review we provide an overview of the Estonian Biobank, highlight its strengths for studying the effects of genetic variation and quantitative phenotypes on health-related traits, development of methods and frameworks for bringing genomics into the clinic, and its role as a driving force for implementing personalized medicine on a national level and beyond.

Breast cancer (BC) remains the most common malignant tumor site and the leading cause of cancer-related deaths in women despite the wide availability of screening programs and personalized treatment options. The BRIGHT study tested a genetic risk-based personalized BC screening service model in women younger than 50 years, using telemedicine and home-based testing. Participants underwent polygenic risk score and monogenic pathogenic variant testing. This type of screening model demonstrated feasibility, clinical utility, and acceptability. It has the potential to enhance BC screening programs, particularly for younger women and those at higher genetic risk, while avoiding unnecessary interventions for low-risk individuals. ### Competing Interest Statement PP has ownership in OU Antegenes. AP, KKK, SS, AP, JP, and NT are receiving salaries from OU Antegenes. PP, KO, AL, LL, LR (Laura Roht), SP, TK, AI, SU, KK, ATT, and NT are receiving salaries from the Tartu University Hospital. ### Clinical Trial ISRCTN29884654 ### Funding Statement This project was supported via the EIT Health BRIGHT innovation activity (project #230121). EIT Health is supported by the European Institute of Innovation and Technology (EIT), a body of the European Union. Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the EIT. Neither the European Union nor the granting authority can be held responsible for them. SP received support from the Estonian Research Council grant PSG774. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Estonian Committee on Bioethics and Human Research gave ethical approval for this work (permission number 1.1-12/1930). Ethics committee of the Portuguese Ethics Committee of the Lisbon Academic Medical Center gave ethical approval for this work (permission number 177/22). Ethics committee of the Swedish Ethical Review Authority gave ethical approval for this work (permission number 2022-03074-01). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All materials used for this study are included in the main or supplementary information files. The participants datasets generated and analyzed during the current study are not publicly available due to reasons of sensitivity but are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at OU Antegenes.

Background: Cancer burden is a globally growing problem. Early diagnosis and targeted treatment decrease patients’ death rate, pain, and treatment expenses. Liquid biopsy can be used for early cancer detection, treatment selection, and progression and treatment response monitoring. We evaluated the performance of circulating cell-free DNA (cfDNA) and formalin-fixed paraffin-embedded (FFPE) tissue DNA analyses using a commonly employed targeted therapeutic pathway in predicting the outcomes of patients with lung cancer, a common cancer with a generally poor prognosis. Methods: Patients with advanced lung cancer (n = 106) and predominantly adenocarcinoma histology donated blood samples at baseline and progression (n = 22), with matched archival FFPE biopsy samples being available for 75 patients. We set up a targeted 21-amplicon sequencing workflow for the analysis of mutations in nine genes (ALK, AKT1, BRAF, EGFR, ERBB2, KRAS, MET, NRAS, and PIK3CA). Molecular characteristics such as cfDNA concentration, number of mutations, and mutation occurrence in specific genes, were analyzed in respect of clinical outcome. To identify factors associated with overall survival (OS), a multivariate analysis was performed, using the technique of Cox regression. Results: The median age of the study population was 67 years with 53.8% male patients. The patients had primarily adenocarcinoma (79.2%) and stage IV disease (83%). The median OS was 327 (95% CI 275–514) days. Higher cfDNA concentrations were associated with poorer OS (HR = 1.670, 95% CI 1.108–2.516, P = 0.014). Detectable mutations [variant allele frequency (VAF) > 0.8%] were found in 63 (59%) patients’ baseline samples (median VAF = 1.1%). OS was significantly improved among patients with at least one mutation detected in cfDNA than among those with no mutation (HR = 0.477, 95% CI 0.313–0.727, P = 0.0006). In baseline cfDNA, patients with mutations of VAFs < 5% had significantly better OS compared to patients with mutations of VAFs ≥ 5% (HR = 3.510, 95% CI 1.672–7.370, P = 0.0009). Patients with slowly progressing disease had significantly more cfDNA mutations than did those with rapid cancer progression (P = 0.045). EGFR alterations explained half (16/33) of slowly progressing cases (median OS 953 days). All associations in FFPE biopsy material were statistically insignificant. *Corresponding author: Neeme Tõnisson, Estonian Genome Centre, Institute of Genomics, University of Tartu, Riia 23b, Tartu 51010, Estonia Check for updates ISSN: 2643-4563 DOI: 10.23937/2643-4563/1710033 Tamm et al. Int J Oncol Res 2022, 5:033 • Page 2 of 13 • Introduction The usefulness of the analysis of circulating cell-free DNA (cfDNA) from blood (“liquid biopsy”) for cancer diagnosis, monitoring, and treatment selection has been firmly established [1-4]. Liquid biopsy is an attractive alternative to more-invasive interventional solid-tissue biopsy for the guidance of therapeutic management based on somatic cancer variants [5]. cfDNA levels or variant allele frequencies (VAFs; fractions of cfDNA harboring a specific alteration) can be monitored longitudinally as potential prognostic biomarkers [6,7]. cfDNA mutation profiling by next-generation sequencing (NGS) has very high sensitivity [8,9]. For example, the incorporation of white blood cells to filter out somatic mutations associated with clonal hematopoiesis can enable the detection of mutations with VAFs below < 1% [10]. In addition, plasma cfDNA sequencing reduces the possibility that clinically relevant mutations in late-stage cancers are missed due to the issue of heterogeneity for biopsies obtained from single metastatic sites [11,12]. cfDNA analysis has been used successfully to identify actionable mutations in the epidermal growth factor receptor (EGFR) gene and other genes for the targeted treatment of non-small cell lung cancer (NSCLC) [1315]. Despite these potential advantages, however, the analysis of DNA from formalin-fixed paraffin-embedded solid-tumor tissue samples (FFPE DNA) remains much more common in the clinical setting. Several challenges associated with the use of cfDNA analysis, such as the accurate quantification and interpretation of VAFs, and the interpretation of variants with consideration of the complexity of the tumor mutational landscape remain [16,17]. Along with the lack of technical standardization, these challenges have led to some skepticism concerning the implementation of cfDNA analysis in daily clinical practice [17,18]. Emerging guidelines and standardized recommendations for cfDNA analysis and liquid biopsy in general are crucial for the development of this field [3,5,19,20]. This study was performed to evaluate the prognostic value of targeted cfDNA analysis relative to that of FFPE DNA analysis for advanced lung cancer. We hypothesized that differences in patients’ cancer progression and overall survival (OS) would be reflected in mutation profiles determined by both methods. We set up an NGS workflow to analyze cancer-related mutations in the nine frequently mutated genes in the EGFR pathway. Genetic findings from cfDNA and FFPE DNA analyses, as well as cfDNA concentrations, were compared with patients’ clinical profiles and therapeutic outcomes.