Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 167 prevalence and impact of pathogenic variants in established breast cancer susceptibility genes, as well as the contributions of newly identified genetic loci from GWAS. Additionally, we will examine the molecular mechanisms by which these genetic alterations influence breast cancer development and progression. Understanding these genetic underpinnings is essential for improving risk assessment, genetic counseling, and the development of targeted therapies. This study also aims to highlight the importance of integrating genetic information into clinical practice to enhance personalized medicine approaches for breast cancer prevention and treatment. By addressing these objectives, we hope to contribute to the ongoing efforts to reduce the global burden of breast cancer through improved genetic insights and clinical applications. 2 Key Genetic Factors in Breast Cancer 2.1 High-penetrance genes: BRCA1 andBRCA2 BRCA1 and BRCA2 are the most well-known high-penetrance genes associated with hereditary breast cancer. Mutations in these genes significantly increase the risk of developing breast cancer, with BRCA1 mutations leading to a lifetime risk of up to 84% and BRCA2 mutations up to 84% by age 70 (Ford et al., 1998). These genes are crucial for DNA repair through homologous recombination, and their loss of function results in genomic instability, which can lead to cancer development (Ford et al., 1998; Sokolova et al., 2023). BRCA1 mutations are particularly associated with triple-negative breast cancer (TNBC), a subtype that lacks estrogen, progesterone, and HER2 receptors, making it more challenging to treat (Woodward et al., 2024). BRCA2 mutations, on the other hand, are more frequently associated with both male and female breast cancer, and they also carry a significant risk for ovarian cancer (Ford et al., 1998). The identification of BRCA1 and BRCA2 mutations has led to the development of targeted therapies, such as PARP inhibitors, which exploit the defective DNA repair mechanisms in these cancer cells (Sokolova et al., 2023). 2.2 Moderate and low-penetrance genes Beyond BRCA1 and BRCA2, several other genes contribute to breast cancer susceptibility, albeit with lower penetrance. These include moderate-penetrance genes like PALB2, CHEK2, and ATM, which play roles in DNA repair and cell cycle regulation. PALB2 (Partner and Localizer of BRCA2) works closely with BRCA2 in DNA repair. Mutations in PALB2 are associated with a moderate increase in breast cancer risk, with an odds ratio of 3.83 (Hu et al., 2021). CHEK2 (Checkpoint Kinase 2) is involved in DNA damage response, and its mutations, such as the 1100delC variant, are linked to a moderate risk of breast cancer, particularly estrogen receptor-positive subtypes (Dorlinget al., 2021; Hu et al., 2021). ATM (Ataxia-Telangiectasia Mutated) is another gene involved in the DNA damage response, and its mutations are associated with an increased risk of breast cancer, especially in estrogen receptor-positive cases (Economopoulou et al., 2015; Dorlinget al., 2021). These genes, while not as penetrant as BRCA1 and BRCA2, still contribute significantly to familial breast cancer risk. For instance, in a study of BRCA1/2 negative families, mutations in ATM and CHEK2 accounted for a substantial proportion of the moderate penetrance mutations identified (Maxwell et al., 2014). Additionally, the presence of these mutations can inform personalized screening and prevention strategies, similar to those developed for BRCA1 and BRCA2 mutation carriers (Gracia-Aznárez et al., 2013; Maxwell et al., 2014). 2.3 Genetic susceptibility and familial risk Familial aggregation of breast cancer suggests a strong genetic component to the disease. While BRCA1 and BRCA2 mutations account for a significant proportion of hereditary breast cancer, they do not explain all familial cases. Studies have shown that a considerable number of families with a history of breast cancer do not have mutations in these genes, indicating the involvement of other genetic factors (Ford et al., 1998; Maxwell et al., 2014). Research has identified several other high and moderate penetrance genes that contribute to familial breast cancer risk. For example, TP53, PTEN, and CDH1 are high-penetrance genes associated with specific cancer syndromes
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