Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 166 Review Article Open Access Genetic Perspectives on the Pathogenesis of Breast Cancer: A Comprehensive Review Liting Wang Hainan Institute of Biotechnology, Haikou, 570206, Hainan, China Corresponding email: liting.wang@hibio.org Cancer Genetics and Epigenetics, 2024, Vol.12, No.4 doi: 10.5376/cge.2024.12.0019 Received: 27May, 2024 Accepted: 02 Jul., 2024 Published: 12 Jul., 2024 Copyright © 2024 Wang, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Wang L.T., 2024, Genetic perspectives on the pathogenesis of breast cancer: a comprehensive review, Cancer Genetics and Epigenetics, 12(4): 166-181 (doi: 10.5376/cge.2024.12.0019) Abstract Breast cancer is a multifaceted disease influenced by a combination of genetic, hormonal, and environmental factors. This study delves into the genetic underpinnings of breast cancer, focusing on high-penetrance mutations in BRCA1 and BRCA2, as well as moderate and low-penetrance genetic variants. The study synthesizes findings from genome-wide association studies (GWAS) and other large-scale collaborative efforts, highlighting the identification of novel susceptibility loci and their potential target genes. Additionally, it explores the role of genetic modifiers in BRCA1/2 carriers and the implications for risk prediction and personalized prevention strategies. The review also addresses the heterogeneity of breast cancer, emphasizing the distinct pathological characteristics of tumors in BRCA1/2 mutation carriers compared to those unselected for family history. By integrating insights from various genetic studies, this study aims to enhance the understanding of breast cancer pathogenesis and inform future research directions and clinical practices. Keywords Breast cancer genetics; BRCA1/BRCA2 mutations; Genome-wide association studies (GWAS); Genetic susceptibility; Risk prediction 1 Introduction Breast cancer is the most commonly diagnosed cancer among women worldwide and represents a significant public health challenge. It is a leading cause of cancer-related mortality, with millions of new cases diagnosed annually. The disease is characterized by its biological and molecular heterogeneity, which complicates diagnosis, treatment, and prognosis (Feng et al., 2018). Breast cancer can originate in different parts of the breast, such as the ducts, lobules, or connective tissues, and it encompasses various subtypes with distinct clinical and pathological features (Feng et al., 2018). The global burden of breast cancer necessitates ongoing research to better understand its etiology and to develop more effective prevention, diagnostic, and therapeutic strategies. Genetic factors play a crucial role in the pathogenesis of breast cancer. A significant proportion of breast cancer cases are attributed to hereditary factors, with pathogenic variants in genes such as BRCA1 and BRCA2 being well-established contributors to increased risk (Breast Cancer Association Consortium, 2021; Hu et al., 2021; Sokolova et al., 2023). These high-penetrance genes are associated with a substantial lifetime risk of developing breast cancer, often leading to early-onset disease (Shiovitz et al., 2015; Sokolova et al., 2023). In addition to BRCA1 and BRCA2, other genes such as ATM, CHEK2, PALB2, RAD51C, RAD51D, and BARD1 have been implicated in breast cancer susceptibility, albeit with varying degrees of risk (Breast Cancer Association Consortium, 2021; Hu et al., 2021; Sokolova et al., 2023). Recent advances in genome-wide association studies (GWAS) have identified numerous common genetic loci associated with breast cancer risk, although the underlying mechanisms and target genes remain largely unknown (Guo et al., 2018). The interplay between genetic predisposition and other factors, such as environmental and lifestyle influences, further complicates the understanding of breast cancer etiology (Mavaddat et al., 2010). This study aims to provide a comprehensive overview of the genetic factors involved in the pathogenesis of breast cancer. By synthesizing findings from recent studies, we aim to elucidate the roles of high-penetrance, moderate-penetrance, and low-penetrance genetic variants in breast cancer risk. This study will explore the
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