Czene, Kamila

Abstract Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke’s R², and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

Image-derived artificial intelligence (AI) risk models have shown promise in short-term risk assessment for improving breast cancer (BC) screening. No image-derived long-term AI risk model for primary prevention has been developed and externally validated. Individuals aged 31 to 94 years were recruited between 2010 and 2020 in two population-based case cohorts (Olmsted County, Minnesota, US, and KARMA, Sweden) and one hospital-based case-control study (EMBED, Atlanta, US). Median follow-up in the case cohorts was 10 years, with BCs diagnosed through June 2022. Additional validation was performed in EMBED with 3-year follow-up. An AI risk model was developed in Sweden, and we report independent validation in Olmsted/KARMA/EMBED. Absolute 10-year risks were estimated at study entry. Time-dependent discriminatory performance [AUC( t )] and expected-to-observed events (E/O) were estimated. Comparisons were performed with clinical risk tools and the image-based Mirai tool. Across Olmsted/KARMA, 8696 individuals (mean age, 54.4±10.6) and 1633 individuals with incident BC (mean age, 57.0±10.6) were included. Average 10-year risks were 3.83 and 3.14%, and E/O ratios were 0.99 and 0.99. Ten-year AUC( t ) for invasive BCs were 0.72 in Olmsted and 0.72 in KARMA. Similar discriminatory results were observed in EMBED. Our AI risk tool performed significantly better than Mirai in Olmsted/KARMA/EMBED. In KARMA, in the top 10% of high-risk individuals, the AI risk tool predicted 33% of BCs compared with 23%/20%/24% predicted by Tyrer-Cuzick-v8/BCSC-v3/Mirai (all P < 0.01). The 10-year image-derived AI risk model showed significantly higher performance than clinical risk models and Mirai in diverse populations, supporting its clinical potential for primary prevention.

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

Abstract Studies have identified genetic and epidemiologic factors associated with mammographic density (MD) phenotypes. However, MD-associated genetic variants only account for a small proportion of the total estimated heritability. Interrogating interactions between genetic and epidemiologic factors could potentially identify additional MD-associated loci, expand our understanding of the genetic basis of MD phenotypes, and clarify how epidemiologic factors modulate relationships between genetic variants and MD. We conducted six separate genome-wide, gene–environment (GxE) interaction analyses, applying 2 degrees of freedom (df) and 1df interaction tests, for each of three MD phenotypes (percent density, dense area (DA), and nondense area (NDA)). The six epidemiologic factors considered were height, ever parous, parity, ever menopausal hormone therapy, ever breastfeeding, and months of breastfeeding. We included European ancestry participants from multiple studies within the Markers of Density consortium and the Breast Cancer Association Consortium (n = 4895-16 218 depending on specific analyses). We identified 11 loci with genome-wide significant (P &lt; 5 × 10−8) interaction tests including two novel common genetic signals interacting with parity (8p21.2) and ever breastfeeding (19p13.2) for NDA. Our results suggest that epidemiologic risk factors might influence relationships between common genetic variants and MD phenotypes at particular genomic loci.

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.

Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Background: Image-derived artificial intelligence (AI) risk models have shown promise in identifying high-risk women in the short term. The long-term performance of image-derived risk models expanded with clinical factors has not been investigated. Methods: We performed a case–cohort study of 8110 women aged 40–74 randomly selected from a Swedish mammography screening cohort initiated in 2010 together with 1661 incident BCs diagnosed before January 2022. The imaging-only AI risk model extracted mammographic features and age at screening. Additional lifestyle/familial risk factors were incorporated into the lifestyle/familial-expanded AI model. Absolute risks were calculated using the two models and the clinical Tyrer–Cuzick v8 model. Age-adjusted model performances were compared across the 10-year follow-up. Results: The AUCs of the lifestyle/familial-expanded AI risk model ranged from 0.75 (95%CI: 0.70–0.80) to 0.68 (95%CI: 0.66–0.69) 1–10 years after study entry. Corresponding AUCs were 0.72 (95%CI: 0.66–0.78) to 0.65 (95%CI: 0.63–0.66) for the imaging-only model and 0.62 (95%CI: 0.55–0.68) to 0.60 (95%CI: 0.58–0.61) for Tyrer–Cuzick v8. The increased performances were observed in multiple risk subgroups and cancer subtypes. Among the 5% of women at highest risk, the PPV was 5.8% using the lifestyle/familial-expanded model compared with 5.3% using the imaging-only model, p < 0.01, and 4.6% for Tyrer–Cuzick, p < 0.01. Conclusions: The lifestyle/familial-expanded AI risk model showed higher performance for both long-term and short-term risk assessment compared with imaging-only and Tyrer–Cuzick models.

PURPOSE Image-derived artificial intelligence–based short-term risk models for breast cancer have shown high discriminatory performance compared with traditional lifestyle/familial-based risk models. The long-term performance of image-derived risk models has not been investigated. METHODS We performed a case-cohort study of 8,604 randomly selected women within a mammography screening cohort initiated in 2010 in Sweden for women age 40-74 years. Mammograms, age, lifestyle, and familial risk factors were collected at study entry. In all, 2,028 incident breast cancers were identified through register matching in May 2022 (206 incident breast cancers were found in the subcohort). The image-based model extracted mammographic features (density, microcalcifications, masses, and left-right breast asymmetries of these features) and age from study entry mammograms. The Tyrer-Cuzick v8 risk model incorporates self-reported lifestyle and familial risk factors and mammographic density to estimate risk. Absolute risks were estimated, and age-adjusted AUC model performances (aAUCs) were compared across the 10-year period. RESULTS The aAUCs of the image-based risk model ranged from 0.74 (95% CI, 0.70 to 0.78) to 0.65 (95% CI, 0.63 to 0.66) for breast cancers developed 1-10 years after study entry; the corresponding Tyrer-Cuzick aAUCs were 0.62 (95% CI, 0.56 to 0.67) to 0.60 (95% CI, 0.58 to 0.61). For symptomatic cancers, the aAUCs for the image-based model were ≥0.75 during the first 3 years. Women with high and low mammographic density showed similar aAUCs. Throughout the 10-year follow-up, 20% of all women with breast cancers were deemed high-risk at study entry by the image-based risk model compared with 7.1% using the lifestyle familial-based model ( P < .01). CONCLUSION The image-based risk model outperformed the Tyrer-Cuzick v8 model for both short-term and long-term risk assessment and could be used to identify women who may benefit from supplemental screening and risk reduction strategies.

Abstract Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09–1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words)