Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 270-278 http://medscipublisher.com/index.php/cge 271 more effective management of esophageal cancer. 2 Molecular Mechanisms of Esophageal Tumorigenesis 2.1 Genetic pathways involved in esophageal cancer progression Esophageal cancer progression is driven by mutations in key genetic pathways, particularly those involved in DNA damage repair, cell cycle regulation, and oncogenic signaling. The p53 pathway is commonly altered, with mutations in TP53 occurring in up to 70% of esophageal squamous cell carcinomas (ESCC), leading to impaired tumor suppression and unchecked cell proliferation (Kishino et al., 2016). Furthermore, the Wnt signaling pathway is often activated through the methylation of its negative regulators, contributing to the dysregulation of cellular growth and differentiation. 2.2 Role of DNA repair mechanisms and genomic instability Alterations in DNA damage repair (DDR) mechanisms are critical contributors to genomic instability and the development of esophageal cancer. The two main pathways for repairing double-strand breaks—homologous recombination (HR) and non-homologous end joining (NHEJ)—are frequently disrupted in esophageal squamous cell cancer. Genes such as RAD51 and XRCC4 are often mutated or amplified, leading to deficient repair processes, which increase susceptibility to cancer progression and therapeutic resistance (Wang et al., 2020). DNA repair defects not only predispose individuals to cancer but also play a significant role in determining treatment outcomes, particularly in radiotherapy and chemotherapy. 2.3 Chromosomal aberrations and gene amplification in tumor development Chromosomal aberrations, including deletions, amplifications, and translocations, are common features of esophageal cancer and drive tumorigenesis by altering critical genes involved in cellular growth and survival. Copy number variations (CNVs) affecting genes such as BRCA2, CHEK2, and RB1 have been identified in ESCC, with gene amplifications frequently associated with poor prognosis (Liu et al., 2022). Additionally, amplifications in DNA repair pathway genes, particularly in the DSB repair mechanisms, exacerbate genomic instability, fueling tumor growth and resistance to treatment. 3 Genetic Risk Factors for Esophageal Cancer 3.1 Key hereditary risk factors and familial predispositions Familial predisposition plays a notable role in the development of esophageal cancer, particularly in esophageal squamous cell carcinoma (ESCC). Several studies have identified inherited genetic variants that contribute to increased susceptibility to ESCC, including mutations in ALDH2, ADH1B, and BRCA2. These mutations are prevalent in populations where ESCC is endemic, such as in East Asia and certain parts of Iran, where genetic predispositions are often compounded by environmental factors like alcohol and tobacco use (Sawada et al., 2016). Familial clustering of esophageal cancer has also been observed in cases where multiple family members exhibit mutations in genes responsible for alcohol metabolism, such as ADH1B and ALDH2 (Yang et al., 2021). 3.2 Common genetic mutations and polymorphisms associated with esophageal cancer Genetic mutations frequently associated with esophageal cancer include mutations in TP53, PIK3CA, NOTCH1, and CDKN2A. Mutations in TP53 are found in both ESCC and esophageal adenocarcinoma (EAC), leading to genomic instability and cancer progression (Watanabe, 2015). Polymorphisms in genes like NEIL2 involved in DNA repair pathways have also been linked to higher risks of Barrett's esophagus (BE) and EAC, suggesting that defective repair mechanisms contribute to carcinogenesis (Buas et al., 2019). Additionally, polymorphisms in ALDH2 and ADH1B, which impair alcohol metabolism, have been identified as major genetic risk factors for ESCC, particularly in East Asian populations, where alcohol consumption is prevalent (Suo et al., 2019). 3.3 Epigenetic modifications and their roles in cancer initiation Epigenetic modifications, such as DNA methylation and histone modifications, play critical roles in the initiation and progression of esophageal cancer. Altered DNA methylation patterns have been observed in key tumor suppressor genes, including CDKN2A, MLH1, and RUNX3, contributing to the silencing of these genes in both ESCC and EAC (Xiao et al., 2019). Furthermore, the involvement of noncoding RNAs, such as microRNAs
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