Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 168 like Li-Fraumeni syndrome, Cowden syndrome, and hereditary diffuse gastric cancer, respectively (Woodward et al., 2024). These genes, although rare, significantly increase the risk of breast cancer when mutated. Moderate penetrance genes such as PALB2, CHEK2, and ATM also play a role in familial breast cancer. A study involving whole exome sequencing of BRCA1/2 negative individuals with high-risk familial breast cancer identified mutations in these genes, highlighting their contribution to genetic susceptibility (Maxwell et al., 2014. Furthermore, a large-scale meta-analysis confirmed the association of these genes with breast cancer risk, providing strong statistical support for their inclusion in genetic testing panels (Suszyńska et al., 2019). The concept of polygenic risk, which involves the cumulative effect of multiple low-penetrance alleles, is also important in understanding familial breast cancer. This polygenic model suggests that the combined effect of many small-risk alleles can significantly contribute to an individual's overall risk of developing breast cancer (Sokolova et al., 2023) (Figure 1). Figure 1 Examples of tumour pathology in hereditary breast cancer (Adopted from Sokolova et al., 2023) Image caption: A, BRCA1-associated invasive carcinoma of no special type with medullary pattern; B, CDH1-associated breast cancer is characteristically invasive lobular carcinoma; C, invasive carcinoma with apocrine differentiation can be associated with germline PTEN mutations (Cowden syndrome) (Adopted from Sokolova et al., 2023) In conclusion, while BRCA1 and BRCA2 are the most well-known genes associated with hereditary breast cancer, other high and moderate penetrance genes also play crucial roles. Understanding the genetic landscape of breast cancer susceptibility can inform personalized risk assessment, screening, and prevention strategies, ultimately improving outcomes for individuals with a familial risk of breast cancer. Large-scale collaborative efforts and advanced genetic testing technologies are essential to further elucidate the genetic factors contributing to breast cancer and to translate these findings into clinical practice (Sokolova et al., 2023). 3 Molecular Pathways and Mechanisms 3.1 Oncogenes and tumor suppressor genes Genetic mutations in oncogenes and tumor suppressor genes play a pivotal role in the pathogenesis of breast cancer. Oncogenes such as MYCand ERBB2 (HER2) are frequently amplified or overexpressed in breast cancer, leading to uncontrolled cell proliferation and tumor growth. MYC, a well-known oncogene, is involved in cell cycle regulation, apoptosis, and cellular transformation. Its overexpression has been linked to poor prognosis and aggressive tumor behavior (Kenemans et al., 2004; Lee and Muller, 2010). Similarly, ERBB2, also known as HER2, is amplified in approximately 20-30% of breast cancers and is associated with increased tumor aggressiveness and poor clinical outcomes (Kenemans et al., 2004; Hu et al., 2009). On the other hand, tumor suppressor genes such as TP53 and BRCA1/2 are often mutated or inactivated in breast cancer. TP53, which encodes the p53 protein, is a critical regulator of the cell cycle and apoptosis. Mutations in TP53 are found in about 30% of breast cancers and are associated with high-grade tumors and poor prognosis (Ingvarsson, 1999; Lee and Muller, 2010). BRCA1 and BRCA2 are involved in DNA repair mechanisms, and their mutations significantly increase the risk of developing breast cancer. These mutations are particularly prevalent in hereditary breast cancers, where they contribute to genomic instability and tumor progression (Kenemans et al., 2004; Feng et al., 2008).
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