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Cancer Genetics and Epigenetics 2024, Vol.12 http://medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher is an international Open Access publisher specializing in cancer genetics, cancer epigenetics, clinical pharmacology, cancer biology at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. Publisher MedSci Publisher Editedby Editorial Team of Cancer Genetics and Epigenetics Email: edit@cge.medscipublisher.com Website: http://www.medscipublisher.com/index.php/cge Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada Cancer Genetics and Epigenetics (ISSN 2369-2995) is an open access, peer reviewed journal published online by MedSci Publisher. The journal is aimed to publish all works in the areas that with quality and originality, with a scope that spans the areas of cancer genetics and cancer epigenetics. It is archived in LAC (Library and Archives Canada) and deposited in CrossRef. The journal has been indexed by ProQuest as well, expected to be indexed by PubMed and other datebases in near future. All the articles published in Cancer Genetics and Epigenetics are Open Access, and are distributed 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. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
Cancer Genetics and Epigenetics (online), 2024, Vol. 12, No. 4 ISSN 2369-2995 http://www.medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Genetic Perspectives on the Pathogenesis of Breast Cancer: A Comprehensive Review Liting Wang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 4, 166-181 The Potential of RNA Interference in Cervical Cancer Therapy Huixian Li, Jianhui Li Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 4, 182-193 Clinical Validation of Non-Invasive Biomarkers in Colon Cancer Diagnosis Yu Li, Shaoqing Wang, Xingjiang Li Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 4, 194-209 Multi-Modal Data Fusion Using AI for Colon Cancer Prediction Jiyun Zhao, Peishen Yu,Yan Zhang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 4, 210-222 Application and Prospects of VHLGene in Kidney Cancer Diagnosis Qiyan Lou, Xiaoying Xu Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 4, 223-233
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
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
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).
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 169 3.2 Hormonal pathways and breast cancer Hormonal pathways, particularly those involving estrogen receptors (ER), play a crucial role in the development and progression of breast cancer. Estrogen receptors are nuclear hormone receptors that, upon binding to estrogen, regulate the expression of genes involved in cell proliferation and survival. Approximately 70% of breast cancers are ER-positive, meaning they express estrogen receptors and rely on estrogen signaling for growth (Feng et al., 2008; Kashyap et al., 2021). The impact of estrogen on breast cancer is multifaceted. Estrogen promotes the proliferation of breast epithelial cells, and its prolonged exposure, such as through hormone replacement therapy, is a known risk factor for breast cancer. Additionally, estrogen signaling can interact with other oncogenic pathways, such as HER2 and PI3K/AKT, to enhance tumor growth and resistance to therapy (Hu et al., 2009; Hazra et al., 2021). Targeting estrogen receptors with therapies such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors has been a cornerstone of breast cancer treatment, particularly for ER-positive tumors (Osborne et al., 2004; Kashyap et al., 2021). 3.3 Signaling pathways in cancer progression Several key signaling pathways are implicated in the progression of breast cancer, including the Wnt/β-catenin and HER2 signaling pathways. The Wnt/β-catenin pathway is involved in regulating cell proliferation, differentiation, and migration. Aberrant activation of this pathway, often through mutations in pathway components or epigenetic modifications, leads to increased β-catenin levels and transcription of target genes that promote tumorigenesis (Feng et al., 2008; Hazra et al., 2021). In breast cancer, dysregulation of the Wnt/β-catenin pathway has been associated with increased tumor aggressiveness and poor prognosis (Hazra et al., 2021). The HER2 signaling pathway, mediated by the ERBB2 gene, is another critical pathway in breast cancer. HER2 is a receptor tyrosine kinase that, when overexpressed, activates downstream signaling cascades such as the PI3K/AKT and MAPK pathways, leading to enhanced cell proliferation, survival, and metastasis (Kenemans et al., 2004; Hu et al., 2009). HER2-positive breast cancers are typically more aggressive and have a higher likelihood of recurrence. Targeted therapies such as trastuzumab (Herceptin) have been developed to inhibit HER2 signaling and have significantly improved outcomes for patients with HER2-positive breast cancer (Osborne et al., 2004; Hu et al., 2009). In summary, the molecular pathogenesis of breast cancer involves a complex interplay of genetic mutations in oncogenes and tumor suppressor genes, hormonal pathways, and key signaling pathways. Understanding these mechanisms is crucial for developing targeted therapies and improving clinical outcomes for breast cancer patients. 4 Genomic and Epigenetic Alterations 4.1 Somatic mutations in breast cancer Breast cancer is a heterogeneous disease characterized by a variety of somatic mutations that differ across its subtypes. Advances in high-throughput sequencing technologies have enabled the detailed molecular characterization of these mutations, revealing a complex landscape of genetic alterations. Somatic mutations in breast cancer include point mutations, insertions, deletions, and copy number variations, which can lead to the activation of oncogenes or the inactivation of tumor suppressor genes (Chakravarthi et al., 2016). For instance, mutations in the TP53 gene are prevalent in triple-negative breast cancer, while PIK3CA mutations are more common in hormone receptor-positive subtypes (Chakravarthi et al., 2016; Calabrese et al., 2020). The Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium has provided a comprehensive catalogue of cancer-associated gene alterations, including those in breast cancer. This study identified numerous somatic single-nucleotide variants and structural variants that drive tumorigenesis (Calabrese et al., 2020). The integration of transcriptome and whole-genome sequencing data has further elucidated the relationship between somatic mutations and gene expression, highlighting the role of non-coding regions in regulating gene activity (Calabrese et al., 2020) (Figure 2).
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 170 Figure 2 Global view of DNA and RNA alterations that affect tumours (Adopted from Calabrese et al., 2020) Image caption: a, The median numbers of different alterations across histotypes. Histotypes are ordered by hierarchical clustering based on the pattern of different types of alteration. Only histotypes with more than 10 donors are shown. Alt., alternative; non-syn, non-synonymous. Cancer-type abbreviations are listed in Supplementary Table 23. b, c, Circular representations of the selected genes significantly co-occurred with B2M (b) and PCBP2 (c). Connecting lines indicate the specific types of co-occurrence of alteration pairs. The inner histograms indicate the frequencies of incidences of different alteration types shown in different colours. d, All 74 Catalogue of Somatic Mutations in Cancer (COSMIC) cancer census genes or PCAWG driver genes that are both frequently and heterogeneously altered across both RNA- and DNA-level alterations. Yellow bars indicate the proportion of samples that had DNA-level alterations, and green bars indicate the proportion of samples with RNA-level alterations. Middle column is the proportion of each alteration type observed for that gene. e, The enrichment of cancer genes within our list of significantly recurrent genes (Adopted from Calabrese et al., 2020) 4.2 Epigenetic modifications Epigenetic modifications play a crucial role in the regulation of gene expression and are pivotal in the pathogenesis of breast cancer. These modifications include DNA methylation, histone modifications, and the involvement of non-coding RNAs. DNA Methylation: DNA methylation typically occurs at CpG islands and is associated with gene silencing. Aberrant DNA methylation patterns, such as hypermethylation of tumor suppressor genes and hypomethylation of oncogenes, are common in breast cancer and contribute to tumorigenesis (Sharma et al., 2010; Baylin and Jones, 2016). For example, hypermethylation of the BRCA1 promoter is frequently observed in sporadic breast cancers, leading to reduced expression of this critical DNA repair gene (Davalos and Esteller, 2023). Histone Modifications: Histone proteins undergo various post-translational modifications, including methylation, acetylation, phosphorylation, and ubiquitination. These modifications can either activate or repress gene transcription. In breast cancer, dysregulation of histone-modifying enzymes, such as histone deacetylases (HDACs) and histone methyltransferases, has been implicated in the aberrant expression of genes involved in cell cycle regulation, apoptosis, and metastasis (Gray et al., 2022; Szczepanek et al., 2023). For instance, overexpression of HDACs can lead to the deacetylation and inactivation of tumor suppressor genes, promoting cancer progression (Szczepanek et al., 2023).
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 171 Non-Coding RNAs: Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are key regulators of gene expression. In breast cancer, miRNAs can function as oncogenes or tumor suppressors by targeting mRNAs for degradation or translational repression (Baylin and Jones, 2016; Davalos and Esteller, 2023). For example, miR-21 is often upregulated in breast cancer and promotes tumor growth by inhibiting the expression of tumor suppressor genes (Szczepanek et al., 2023). Conversely, miR-34 acts as a tumor suppressor and its downregulation is associated with poor prognosis. 4.3 Interaction between genomic and epigenetic factors The interplay between genomic and epigenetic alterations is a critical aspect of breast cancer pathogenesis. Epigenetic changes can influence genomic stability and contribute to the accumulation of genetic mutations. Epigenetic Regulation of DNA Repair Genes: Epigenetic modifications can affect the expression of genes involved in DNA repair mechanisms. For instance, hypermethylation of the BRCA1 promoter leads to reduced expression of this gene, impairing the homologous recombination repair pathway and increasing the likelihood of genomic instability (Davalos and Esteller, 2023). This can result in the accumulation of mutations and chromosomal aberrations, driving cancer progression (You et al., 2012). Histone Modifications and Chromatin Structure: Histone modifications can alter chromatin structure and accessibility, influencing the repair of DNA damage. For example, histone acetylation generally leads to an open chromatin conformation, facilitating the access of DNA repair machinery to damaged sites. Conversely, histone deacetylation can result in a closed chromatin state, hindering DNA repair processes and promoting genomic instability (Sharma et al., 2010; Gray et al., 2022). Non-Coding RNAs and Genomic Stability: Non-coding RNAs also play a role in maintaining genomic stability. miRNAs can regulate the expression of genes involved in DNA damage response and repair. Dysregulation of these miRNAs can lead to defective DNA repair and increased mutation rates (Baylin and Jones, 2016; Szczepanek et al., 2023). For example, the downregulation of miR-34, which targets genes involved in cell cycle regulation and apoptosis, can contribute to genomic instability and cancer progression. In conclusion, the intricate interplay between genomic and epigenetic alterations is fundamental to the pathogenesis of breast cancer. Understanding these interactions provides valuable insights into the mechanisms driving tumorigenesis and offers potential avenues for therapeutic intervention. 5 Genetic Heterogeneity and Subtype Specificity 5.1 Luminal subtypes and genetic features Luminal subtypes of breast cancer, specifically Luminal A and Luminal B, are characterized by distinct genetic profiles that influence their behavior and response to treatment. Luminal A tumors generally exhibit lower proliferation rates and better prognosis compared to Luminal B tumors. Genetic alterations commonly observed in Luminal A subtypes include mutations in the PIK3CA gene and low expression of proliferation-related genes. These tumors are typically hormone receptor-positive (HR+) and HER2-negative, which makes them responsive to endocrine therapies (Prat et al., 2015). In contrast, Luminal B tumors are more aggressive, with higher proliferation rates and a worse prognosis. They often exhibit higher expression of proliferation-related genes and may also present with PIK3CA mutations, although at a lower frequency compared to Luminal A. Additionally, Luminal B tumors can be either HER2-positive or HER2-negative, which influences their treatment strategies. The presence of HER2 amplification in Luminal B tumors necessitates the use of HER2-targeted therapies in addition to endocrine treatments (Prat et al., 2015). 5.2 HER2-Enriched subtype HER2-positive breast cancer is a heterogeneous disease that includes various intrinsic molecular subtypes, with the HER2-enriched (HER2-E) subtype being the most prevalent. HER2-E tumors are characterized by high expression of genes located near the HER2 amplicon on chromosome 17, including ERBB2, which encodes the
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 172 HER2 protein. These tumors often exhibit alterations in the PI3K/Akt/mTOR pathway, which can predict responsiveness to targeted therapies such as PI3K and mTOR inhibitors (Schettini and Prat, 2021). Clinically, HER2-E tumors are associated with higher rates of pathological complete response (pCR) following neoadjuvant anti-HER2 therapies, such as trastuzumab and lapatinib, especially when used in combination with chemotherapy. This subtype is also linked to a higher likelihood of achieving pCR in hormone receptor-negative (HR-) cases compared to hormone receptor-positive (HR+) cases (Llombart-Cussac et al., 2017; Schettini et al., 2020). The presence of tumor-infiltrating lymphocytes (TILs) in HER2-E tumors further predicts a favorable response to neoadjuvant anti-HER2 treatments and may have prognostic significance (Schettini and Prat, 2021) (Figure 3). Figure 3 HER2-dependent pathway for proliferation and survival in HER2+ breast cancer (Adopted from Schettini and Prat, 2021) Image caption: Legend. cHER2+: clinically HER2-positive; HER2-E: HER2-Enriched. The red cone visually suggests a higher activation of the HER2-related pathway in cHER2+/HER2-E tumors, compared to cHER2+/non-HER2-E (Adopted from Schettini and Prat, 2021) The clinical implications of HER2-E tumors extend to the potential for de-escalation or escalation of systemic therapies based on the genomic profile. For instance, patients with HER2-E tumors may benefit from dual HER2 blockade without chemotherapy, as demonstrated in the PAMELA trial, where HER2-E status predicted a higher pCR rate with trastuzumab and lapatinib alone (Llombart-Cussac et al., 2017). Additionally, novel HER2-targeted therapies, such as antibody-drug conjugates, show promise in treating HER2-E tumors, even those with low HER2 expression (Schettini and Prat, 2021). 5.3 Triple-Negative breast cancer (TNBC) Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. This subtype is associated with a poor prognosis and limited treatment options, primarily relying on chemotherapy (Lehmann and Pietenpol, 2015; Prat et al., 2015). Genomic and transcriptomic analyses have revealed distinct subtypes within TNBC, each with unique genetic and molecular features. These subtypes include luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed, and mesenchymal-like. The LAR subtype, for example, is characterized by the presence of ERBB2 somatic mutations and frequent CDKN2A loss, which may serve as potential therapeutic targets (Jiang et al., 2019). The basal-like subtype, which predominates in TNBC, is associated with high expression of cell cycle and DNA damage response genes, making it more responsive to DNA-damaging agents like cisplatin (Lehmann et al., 2011). The aggressive nature of TNBC is partly due to its high genomic instability and the presence of multiple genetic alterations, including mutations in the TP53 gene and copy number variations. These genetic features contribute to the rapid progression and poor clinical outcomes associated with TNBC (Lehmann and Pietenpol, 2015; Jiang et
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 173 al., 2019). Furthermore, the lack of targeted therapies for TNBC underscores the need for continued research into the molecular underpinnings of this subtype to identify novel therapeutic targets and improve patient outcomes. In summary, the genetic heterogeneity and subtype specificity of breast cancer significantly influence the pathogenesis, prognosis, and treatment strategies for each subtype. Understanding these genetic features is crucial for developing personalized treatment approaches and improving clinical outcomes for breast cancer patients. 6 Genomic Technologies and Their Impact on Breast Cancer Research 6.1 Next-Generation sequencing (NGS) Next-Generation Sequencing (NGS) has revolutionized the field of genomics, providing unprecedented insights into the genetic underpinnings of breast cancer. NGS allows for the rapid sequencing of millions of DNA fragments simultaneously, offering a comprehensive view of the genome. This technology has been instrumental in identifying novel genetic mutations associated with breast cancer, which were previously undetectable with traditional sequencing methods. NGS has enabled the discovery of new driver and passenger mutations, rare chromosomal rearrangements, and other genomic aberrations in breast cancer. For instance, whole genome and exome sequencing have revealed the complex genomic architecture of breast cancer, identifying mutations in genes such as TP53, PIK3CA, and BRCA2, among others (Wheler et al., 2013; Verigos and Magklara, 2015). These findings have significant implications for understanding the molecular mechanisms driving breast cancer and for developing targeted therapies. Moreover, NGS has facilitated the identification of unique genomic profiles in breast cancer patients, which can be correlated with their response to targeted therapies. For example, a study involving 57 patients with advanced or metastatic breast cancer demonstrated that NGS profiling could identify specific molecular aberrations that were prognostic and predictive of treatment response (Wheler et al., 2013). This highlights the potential of NGS to personalize breast cancer treatment, improving patient outcomes. 6.2 CRISPR-Cas9 and gene editing The advent of CRISPR-Cas9 technology has opened new avenues for gene editing in breast cancer research. CRISPR-Cas9 allows for precise modifications of the genome, enabling researchers to investigate the functional roles of specific genes in breast cancer development and progression. This technology holds great promise for identifying new therapeutic targets and for developing gene-based therapies. One of the significant potentials of CRISPR-Cas9 in breast cancer research is its ability to create knockout models to study the effects of gene loss-of-function. This can help in understanding the role of tumor suppressor genes and identifying potential vulnerabilities in cancer cells. Additionally, CRISPR-Cas9 can be used to introduce specific mutations into the genome, mimicking the genetic alterations observed in breast cancer patients. This can provide valuable insights into the molecular mechanisms driving the disease and aid in the development of targeted therapies. However, the application of CRISPR-Cas9 in breast cancer research is not without challenges. One of the primary concerns is the off-target effects, where unintended genomic modifications can occur, potentially leading to undesirable consequences. Ensuring the specificity and efficiency of CRISPR-Cas9 is crucial for its safe and effective use in clinical settings. Additionally, the delivery of CRISPR-Cas9 components to target cells in vivo remains a significant hurdle, requiring the development of efficient and targeted delivery systems. 6.3 Liquid biopsies and genomic profiling Liquid biopsies have emerged as a promising non-invasive tool for monitoring genetic mutations and treatment response in breast cancer. This technique involves the analysis of circulating tumor DNA (ctDNA) in the blood, providing a real-time molecular profile of the tumor. Liquid biopsies offer several advantages over traditional tissue biopsies, including the ability to capture tumor heterogeneity and to monitor disease progression and treatment response dynamically.
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 174 NGS has been instrumental in advancing the application of liquid biopsies in breast cancer. By sequencing ctDNA, researchers can detect genetic mutations and alterations associated with breast cancer, even at low frequencies. This enables early detection of cancer, monitoring of minimal residual disease, and identification of emerging resistance mutations during treatment (Chen and Zhao, 2019; Esagian et al., 2020). For instance, a study demonstrated that NGS-based liquid biopsy could identify clinically relevant mutations in advanced non-small cell lung cancer, highlighting its potential applicability in breast cancer as well (Esagian et al., 2020). Despite its promise, the implementation of liquid biopsies in clinical practice faces several challenges. One of the primary issues is the sensitivity and specificity of ctDNA detection, particularly in early-stage cancers where the ctDNA levels are low. Additionally, standardizing the methodologies and ensuring the reproducibility of results across different platforms and laboratories is crucial for the widespread adoption of liquid biopsies in clinical settings. In conclusion, genomic technologies such as NGS, CRISPR-Cas9, and liquid biopsies are transforming breast cancer research. These technologies are providing deeper insights into the genetic landscape of breast cancer, identifying novel mutations, and enabling personalized treatment approaches. However, addressing the associated challenges is essential to fully realize their potential in improving breast cancer diagnosis, treatment, and patient outcomes. 7 Genetic Testing and Personalized Medicine in Breast Cancer 7.1 Genetic counseling and testing guidelines Genetic counseling and testing have become integral components of breast cancer management, particularly for individuals with a family history of the disease or known genetic predispositions. Current practices emphasize the importance of genetic counseling both before and after testing to ensure patients understand the implications of their results. For instance, the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) have developed guidelines to assist healthcare providers in making informed decisions about genetic testing and counseling (Hampel et al., 2015). These guidelines recommend genetic counseling at multiple points in the care pathway, although the format and timing can vary across different regions and institutions (Forbes et al., 2019). Despite these recommendations, there are significant challenges in the implementation of genetic testing. One major issue is the underutilization of genetic counseling services. Studies have shown that a substantial proportion of eligible patients are not referred for genetic counseling, which can lead to missed opportunities for early intervention and personalized treatment (Heller et al., 2021; Mendenhall et al., 2024). Additionally, there is a shortage of trained genetic counselors, which is expected to worsen as the demand for genetic testing increases (Singer et al., 2019). This shortage can compromise the quality of care and delay the integration of genetic information into clinical practice. 7.2 Personalized treatment approaches The role of genetic information in guiding targeted therapies for breast cancer is increasingly recognized. Advances in cancer genetics and genomics have enabled the identification of specific mutations that can be targeted with precision therapies. For example, BRCA1 and BRCA2 mutations are well-known markers that can influence treatment decisions, including the use of poly(ADP-ribose) polymerase (PARP) inhibitors (Dancey et al., 2012; Forbes et al., 2019). These targeted therapies have shown promise in improving outcomes for patients with specific genetic profiles. Moreover, the integration of genetic testing into clinical practice allows for more personalized treatment plans. Genetic information can guide decisions regarding the use of chemotherapy, radiotherapy, and surgical interventions. For instance, patients with certain genetic mutations may benefit from more aggressive treatment strategies or prophylactic surgeries to reduce the risk of cancer recurrence (Mendenhall et al., 2024). The use of multigene panel testing has further expanded the scope of genetic information available, enabling the identification of additional mutations that may influence treatment decisions (Heller et al., 2021).
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 175 7.3 Case studies and clinical trials Several case studies and clinical trials have demonstrated the benefits of personalized medicine approaches in breast cancer. One notable example is the study conducted by Kawaguchi-Sakita et al., which evaluated the impact of genetic counseling on patients with hereditary breast cancer. The study found that genetic counseling significantly improved patients' understanding and management of their condition, as measured by the Genetic Counseling Outcome Scale (GCOS-24) (Kawaguchi et al., 2023). This study highlights the importance of genetic counseling in empowering patients and facilitating informed decision-making. Another example is the Making Genetic Testing Accessible (MAGENTA) trial, which assessed the impact of omitting pretest and posttest genetic counseling on patient distress during remote genetic testing. The trial found that omitting counseling did not increase distress, suggesting that alternative models of genetic risk assessment, such as remote testing, can be effective and may help overcome barriers to access (Swisher et al., 2023). This finding is particularly relevant in the context of the ongoing shortage of genetic counselors. Additionally, a randomized controlled trial conducted in Mexico City compared the effectiveness of a pretest educational video to in-person genetic counseling. The study found that the educational video was non-inferior to in-person counseling in terms of genetic testing acceptance, knowledge improvement, and anxiety reduction (Guerra et al., 2023). These results support the use of innovative approaches to genetic counseling, particularly in resource-limited settings. In conclusion, genetic testing and personalized medicine are transforming the landscape of breast cancer treatment. While there are challenges in the implementation of genetic counseling and testing, ongoing research and innovative approaches are helping to address these issues and improve patient outcomes. The integration of genetic information into clinical practice enables more targeted and effective therapies, ultimately enhancing the quality of care for breast cancer patients. 8 Ethical, Legal, and Social Implications of Genetic Research in Breast Cancer 8.1 Ethical considerations in genetic testing Genetic testing for breast cancer susceptibility, particularly involving BRCA1 and BRCA2 mutations, presents numerous ethical dilemmas. One significant issue is the "duty to warn" relatives about inherited cancer risks. This raises questions about the balance between patient confidentiality and the potential benefits of informing family members who might also be at risk (Offit and Thom, 2007). Additionally, the appropriateness of testing children and embryos for genetic predispositions is contentious, as it involves making decisions that could impact an individual's future autonomy and psychological well-being (Surbone, 2001; Offit and Thom, 2007). The psychological impact of genetic knowledge is another ethical concern. Some women may experience significant anxiety and stress upon learning their genetic risk, which can affect their quality of life and decision-making processes regarding preventive measures such as prophylactic surgeries (Surbone, 2001). Conversely, others may find empowerment in this knowledge, using it to make informed decisions about their health and lifestyle (Surbone, 2001). The ethical challenge lies in ensuring that individuals are fully informed and supported throughout the testing process to make decisions that align with their values and preferences. 8.2 Legal frameworks and genetic information The legal landscape surrounding genetic testing for breast cancer is complex and varies by jurisdiction. One of the primary legal concerns is genetic discrimination, where individuals may face unfair treatment based on their genetic information. This can occur in various contexts, including employment and insurance. For instance, individuals with a known genetic predisposition to breast cancer might be denied health insurance coverage or charged higher premiums, which raises significant ethical and legal questions about equity and justice (Ee, 1998; Offit and Thom, 2007). Privacy issues are also paramount in the context of genetic testing. The handling and sharing of genetic information must be carefully managed to protect individuals' privacy. The use of electronic health records and
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 176 data sharing practices must comply with stringent privacy laws to prevent unauthorized access and misuse of genetic data (Hammer, 2019). Ensuring informed consent is critical, where patients must be fully aware of how their genetic information will be used, stored, and shared (Hammer, 2019). 8.3 Social implications and public perception The social implications of genetic testing for breast cancer are profound, affecting patients' social identity and relationships. Knowledge of a genetic predisposition can alter how individuals perceive themselves and how they are perceived by others. For some, this information can lead to a sense of stigma or social isolation, particularly in communities where there is limited understanding or acceptance of genetic conditions (Tamimi et al., 2023). Fear of social stigma can also deter individuals from undergoing genetic testing, even when it could provide significant health benefits (Tamimi et al., 2023). Moreover, genetic information can impact family dynamics. The knowledge that one carries a hereditary risk for breast cancer can lead to complex emotional responses within families, including guilt, anxiety, and changes in familial roles and responsibilities (Surbone, 2001; Neves et al., 2022). For instance, individuals may feel a moral obligation to inform relatives about potential risks, which can strain relationships, especially if family members react negatively or with denial (Neves et al., 2022). Public perception of genetic testing is also influenced by broader societal attitudes towards genetics and disease. There is a need for public education to improve understanding and acceptance of genetic testing, which can help mitigate fears and misconceptions. Effective communication strategies are essential to convey the benefits and limitations of genetic testing, ensuring that individuals can make informed decisions without undue influence from societal pressures (Thapa et al., 2020). In conclusion, the ethical, legal, and social implications of genetic research in breast cancer are multifaceted and require careful consideration. Addressing these issues involves balancing the benefits of genetic knowledge with the potential risks and ensuring that individuals are supported throughout the testing process. Legal protections against discrimination and robust privacy measures are essential to safeguard individuals' rights, while public education and support can help mitigate the social impacts of genetic information. 9 Future Directions in Genetic Research on Breast Cancer 9.1 Emerging genetic targets and therapies The identification of new genetic targets for therapy and prevention is a rapidly evolving area in breast cancer research. Recent advances in whole exome sequencing and multigene panels have enabled the discovery of numerous genetic mutations associated with breast cancer, which can be targeted for therapeutic intervention. For instance, mutations in BRCA1/2, PIK3CA, and other genes have been identified as significant contributors to breast cancer pathogenesis, and targeting these mutations has shown promise in clinical trials (Lima et al., 2019; Hong and Xu, 2022). Additionally, genome-wide association studies (GWAS) have identified over 150 common genetic loci associated with breast cancer risk, providing a rich source of potential targets for new therapies (Guo et al., 2018). Targeted therapies, such as poly(ADP-ribose) polymerase (PARP) inhibitors for BRCA1/2 deficient tumors, have already transformed the treatment landscape for certain breast cancer subtypes (Campeau et al., 2008). Moreover, the role of epigenetic modifiers in breast cancer pathogenesis is gaining attention, with enzymes that modify histone proteins emerging as potential therapeutic targets (Lee et al., 2023). These findings underscore the importance of continuing to explore genetic and epigenetic alterations in breast cancer to develop more effective and personalized treatment strategies. 9.2 Challenges and opportunities Despite significant progress, several challenges remain in the field of genetic research on breast cancer. One major challenge is the heterogeneity of breast cancer, which complicates the identification of universally effective genetic targets (Baliu-Piqué et al., 2020). Tumor heterogeneity, driven by both genetic and non-genetic factors,
Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 177 can lead to therapeutic resistance and variable patient outcomes. Addressing this challenge requires a deeper understanding of the molecular mechanisms underlying tumor heterogeneity and the development of strategies to overcome resistance (Eccles et al., 2013; Baliu-Piqué et al., 2020). Another challenge is the need for more comprehensive and clinically relevant models to study breast cancer. Enhanced resources to support in vitro and in vivo tumor models, as well as improved access to annotated clinical samples, are critical for advancing translational research. Additionally, there is a need for validated biomarkers to predict therapeutic response and guide treatment decisions. Developing and standardizing these biomarkers will be essential for the successful implementation of personalized medicine in breast cancer care (Eccles et al., 2013). Opportunities for advancing genetic research in breast cancer include the integration of new technologies and methodologies. For example, the use of CRISPR-Cas9 for gene editing and the application of single-cell sequencing techniques can provide new insights into the genetic and epigenetic landscape of breast cancer. These technologies have the potential to uncover novel therapeutic targets and improve our understanding of tumor biology (Lima et al., 2019; Waarts et al., 2022). 9.3 The role of AI and big data Artificial intelligence (AI) and big data are poised to revolutionize genetic research in breast cancer by enabling the analysis of large and complex datasets. AI algorithms can identify patterns and correlations in genetic data that may be missed by traditional analytical methods, leading to the discovery of new genetic targets and biomarkers. For instance, machine learning techniques can be used to predict patient outcomes based on genetic profiles, helping to tailor treatment strategies to individual patients (Waarts et al., 2022). Big data initiatives, such as The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project, provide valuable resources for genetic research. These databases contain vast amounts of genomic, transcriptomic, and clinical data that can be leveraged to gain insights into the genetic basis of breast cancer (Guo et al., 2018). By integrating data from multiple sources, researchers can develop more comprehensive models of breast cancer pathogenesis and identify new opportunities for intervention. Moreover, AI can facilitate the development of predictive models for breast cancer risk and progression. By analyzing genetic and clinical data, AI algorithms can identify individuals at high risk for developing breast cancer and recommend preventive measures. This approach has the potential to improve early detection and reduce the burden of breast cancer on healthcare systems (Koldehoff et al., 2021). In conclusion, the future of genetic research in breast cancer lies in the identification of new genetic targets, addressing current research gaps, and leveraging AI and big data to enhance our understanding and treatment of the disease. Continued investment in these areas will be essential for developing more effective and personalized therapies, ultimately improving outcomes for breast cancer patients. 10 Concluding Remarks The genetic landscape of breast cancer is complex and multifaceted, involving a variety of high, moderate, and low-penetrance genes. Pathogenic variants in BRCA1 and BRCA2 are strongly associated with a high risk of breast cancer, with odds ratios of 7.62 and 5.23, respectively. Other significant genes include PALB2, BARD1, RAD51C, RAD51D, ATM, CDH1, and CHEK2, each contributing to varying degrees of risk depending on the breast cancer subtype. Genome-wide association studies (GWAS) have identified over 150 common genetic loci for breast cancer risk, yet the target genes and mechanisms remain largely unknown. The prevalence of pathogenic variants and variants of unknown significance (VUS) is notably high, emphasizing the need for better classification and understanding of these variants. The identification of pathogenic variants in breast cancer susceptibility genes has significant implications for clinical practice. Genetic testing can inform personalized risk assessment and management strategies, enabling targeted screening and preventive measures for high-risk individuals. The use of gene panels in clinical settings has become more common, but the high prevalence of VUS poses challenges for clinical decision-making.
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