BACKGROUND:Population-based mammographic screening is primarily age-based. However, breast cancer risk is multifactorial, and women may benefit from personalized risk-based screening. This pilot study aimed to explore the use of polygenic risk score (PRS) as a tool for risk stratification in personalized screening. METHODS:We included 80 women aged 40-49 years referred for clinical mammography. Exclusion criteria were prior breast cancer or premalignant breast disease, and previous genetic testing. After DNA collection, PRS was calculated from 2805 Single Nucleotide Polymorphisms (SNPs). Screening recommendations were based on each participant's relative 10-year breast cancer risk estimated from PRS and compared with the 10-year risk of an average woman of the same age. Women with a self-reported family history of cancer meeting standard criteria were referred for gene panel testing for pathogenic variants in high-risk genes. A follow up questionnaire regarding participants' experiences was distributed 6-9 months after PRS testing. RESULTS:Mean age was 45.2 years (SD 2.8). Mean relative 10-year breast cancer risk was 1.18 (SD 0.57). Based on PRS, 40 participants were recommended standard biennial screening 50-69 years, while 40 were advised to begin biennial screening before age 50. Among these, 7 were recommended annual mammography from when their 10-year risk reached twice that of an average 50-year-old. Twenty-one women underwent gene panel testing; no pathogenic variants in breast cancer genes were identified. Five women were advised annual mammography from 40-60 years due to family history of breast cancer, regardless of PRS. Most respondents viewed breast cancer risk assessment positively and did not report increased anxiety after testing. CONCLUSIONS:In this pilot cohort, PRS-based risk stratification led to earlier or more intensive screening recommendations in half of the participants, while family history also influenced management.

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.

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.

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.

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: Statistical associations of numerous single nucleotide polymorphisms with breast cancer (BC) have been identified in genome-wide association studies (GWAS). Recent evidence suggests that a Polygenic Risk Score (PRS) can be a useful risk stratification instrument for a BC screening strategy, and a PRS test has been developed for clinical use. The performance of the PRS is yet unknown in the Norwegian population. Aim: To evaluate the performance of PRS models for BC in a Norwegian dataset. Methods: We investigated a sample of 1053 BC cases and 7094 controls from different regions of Norway. PRS values were calculated using four PRS models, and their performance was evaluated by the area under the curve (AUC) and the odds ratio (OR). The effect of the PRS on the age of onset of BC was determined by a Cox regression model, and the lifetime absolute risk of developing BC was calculated using the iCare tool. Results: The best performing PRS model included 3820 SNPs, which yielded an AUC = 0.625 and an OR = 1.567 per one standard deviation increase. The PRS values of the samples correlate with an increased risk of BC, with a hazard ratio of 1.494 per one standard deviation increase (95% confidence interval of 1.406-1.588). The individuals in the highest decile of the PRS have at least twice the risk of developing BC compared to the individuals with a median PRS. The results in this study with Norwegian samples are coherent with the findings in the study conducted using Estonian and UK Biobank samples. Conclusion: The previously validated PRS models have a similar observed accuracy in the Norwegian data as in the UK and Estonian populations. A PRS provides a meaningful association with the age of onset of BC and lifetime risk. Therefore, as suggested in Estonia, a PRS may also be integrated into the screening strategy for BC in Norway.

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150,134 European ancestry individuals and sought significant evidence for independent replication in a further 228,245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9 and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12,607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in BP regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

RNA degradation is a ubiquitous process that occurs in living and dead cells, as well as during handling and storage of extracted RNA. Reduced RNA quality caused by degradation is an established source of uncertainty for all RNA-based gene expression quantification techniques. RNA sequencing is an increasingly preferred method for transcriptome analyses, and dependence of its results on input RNA integrity is of significant practical importance. This study aimed to characterize the effects of varying input RNA integrity [estimated as RNA integrity number (RIN)] on transcript level estimates and delineate the characteristic differences between transcripts that differ in degradation rate. The study used ribodepleted total RNA sequencing data from a real-life clinically collected set (n = 32) of human solid tissue (placenta) samples. RIN-dependent alterations in gene expression profiles were quantified by using DESeq2 software. Our results indicate that small differences in RNA integrity affect gene expression quantification by introducing a moderate and pervasive bias in expression level estimates that significantly affected 8.1% of studied genes. The rapidly degrading transcript pool was enriched in pseudogenes, short noncoding RNAs, and transcripts with extended 3' untranslated regions. Typical slowly degrading transcripts (median length, 2389 nt) represented protein coding genes with 4-10 exons and high guanine-cytosine content.-Reiman, M., Laan, M., Rull, K., Sõber, S. Effects of RNA integrity on transcript quantification by total RNA sequencing of clinically collected human placental samples.

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

We have previously shown an extensive load of somatic copy number variations (CNVs) in the human placental genome with the highest fraction detected in normal term pregnancies. Hereby, we hypothesized that insufficient promotion of CNVs may impair placental development and lead to recurrent pregnancy loss (RPL). RPL affects ~3% of couples aiming at childbirth and idiopathic RPL represents ~50% of cases. We analysed placental and parental CNV profiles of idiopathic RPL trios (mother-father-placenta) and duos (mother-placenta). Consistent with the hypothesis, the placental genomes of RPL cases exhibited 2-fold less CNVs compared to uncomplicated 1st trimester pregnancies (P = 0.02). This difference mainly arose from lower number of duplications. Overall, 1st trimester control placentas shared only 5.3% of identified CNV regions with RPL cases, whereas the respective fraction with term placentas was 35.1% (P = 1.1 × 10−9). Disruption of the genes NUP98 (embryonic stem cell development) and MTRR (folate metabolism) was detected exclusively in RPL placentas, potentially indicative to novel loci implicated in RPL. Interestingly, genes with higher overall expression were prone to deletions (>3-fold higher median expression compared to genes unaffected by CNVs, P = 6.69 × 10−20). Additionally, large pericentromeric and subtelomeric CNVs in parental genomes emerged as a risk factor for RPL.