Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 279-293 http://medscipublisher.com/index.php/cge 284 2023). Additionally, BRCA status can influence the selection of targeted therapies, such as PARP inhibitors, which are particularly effective in BRCA-mutated cancers. However, several challenges remain in the clinical implementation of BRCA testing. One major issue is the interpretation of variants of uncertain significance (VUS). A systematic assessment of 1,433 VUS in the BRCA genes highlighted the difficulty in determining their clinical relevance, which can complicate genetic counseling and decision-making (Easton et al., 2007). Furthermore, the psychological impact of genetic testing and the potential for anxiety and distress among patients must be carefully managed through comprehensive pre- and post-test counseling (Nelson et al., 2005). Addressing these challenges is essential to maximize the benefits of BRCA testing and ensure that patients receive accurate and actionable information. 5 Application of Polygenic Risk Scores (PRS) in Breast Cancer 5.1 Basic principles of PRS and its use in breast cancer risk assessment Polygenic Risk Scores (PRS) are calculated by aggregating the effects of numerous genetic variants, known as single nucleotide polymorphisms (SNPs), each contributing a small amount to the overall risk of developing a disease. In the context of breast cancer, PRS can be derived from genome-wide association studies (GWAS) that identify SNPs associated with the disease. These scores provide an estimate of an individual's genetic susceptibility to breast cancer by summing the weighted effects of these SNPs (Lewis and Vassos, 2020; Wray et al., 2020). The utility of PRS in breast cancer risk assessment lies in its ability to stratify individuals based on their genetic risk. For instance, women with higher PRS are at a significantly increased risk of developing breast cancer compared to those with lower scores. This stratification can be particularly useful in identifying individuals who may benefit from more intensive screening and preventive measures. Studies have shown that PRS can predict breast cancer risk with reasonable accuracy, making it a valuable tool in personalized medicine (Mavaddat et al., 2018; Shieh et al., 2023). 5.2 Risk prediction models combining PRS with environmental factors Combining PRS with environmental and lifestyle factors can enhance the predictive power of breast cancer risk models. Environmental factors such as reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height, and body mass index (BMI) have been shown to interact with genetic risk factors, thereby influencing the overall risk of developing breast cancer (Rudolph et al., 2018). By integrating these factors into risk prediction models, researchers can achieve better discriminatory accuracy compared to models that use PRS alone (Lambert et al., 2019; MBUYA-BIENGE et al., 2023). For example, a study evaluating the joint associations of a 77-SNP PRS with various environmental risk factors found that the combined effects are generally well described by a multiplicative model. This means that the risk associated with environmental factors can be multiplied by the genetic risk to provide a more comprehensive risk assessment. Such models have shown improved performance in predicting breast cancer risk, particularly for estrogen receptor (ER)-positive disease (Rudolph et al., 2018). This approach underscores the importance of considering both genetic and non-genetic factors in breast cancer risk prediction. 5.3 Potential and limitations of PRS in breast cancer screening strategies The potential of PRS in breast cancer screening lies in its ability to identify high-risk individuals who may benefit from early and more frequent screening. For instance, women in the highest percentiles of PRS have been found to have a significantly higher lifetime risk of developing breast cancer, making them prime candidates for targeted screening programs (Mavaddat et al., 2018; Jia et al., 2020). This targeted approach can lead to earlier detection and better outcomes for those at the highest risk. However, there are limitations to the use of PRS in clinical practice. One major limitation is the current discriminative ability of PRS, which is still relatively low in the general population. PRS alone cannot definitively predict future diagnoses of breast cancer, as genetic factors only contribute part of the risk (Lewis and Vassos,
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