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Genomic Instability is Widespread in Esophageal Squamous Dysplasia and Increases During the Progression to Cancer

Year: 2025

Type: article

Abstract: Background: Research on the molecular progression of esophageal squamous dysplasia to cancer remains limited. The majority of prior studies have focused on morphological precancerous lesions sampled adjacent to tumors, and have relied primarily on the analysis of data from whole-exome sequencing. Methods: To investigate the development of esophageal squamous cell carcinoma (ESCC), whole genome analysis was conducted on 13 precancerous tissues and 15 ESCC tissues. Field effects were avoided by using biopsies of squamous dysplasia from patients without concurrent tumor, thereby allowing study of molecular alterations associated with the true precancerous state. Results: Our results revealed frequent copy number alterations (CNAs) and structural variants (SVs) in esophageal squamous dysplasia. These changes were also detected in ESCC, indicating that genomic instability markers such as CNAs and SVs occur at an early stage and persist throughout ESCC evolution. The detection of TP53 mutations and CASP8 deletions in both premalignant lesions and ESCC suggests they may be early driving events during esophageal carcinogenesis. Mutations in MUC5B were observed in 7.7% of precancerous lesions and 6.7% of ESCC. Moreover, these mutations were associated with a higher tumor mutational burden (TMB) and an immune “hot” tumor microenvironment. Apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) enzyme-associated mutational signatures were exclusively identified in ESCC and may further exacerbate genomic instability in the more advanced stages of tumorigenesis. Significantly higher ploidy alterations levels were detected in ESCC compared to squamous dysplasia. Moreover, the cohort that underwent local recurrence of dysplasia within two years had significantly elevated ploidy alterations levels compared to those with no long-term recurrence. These results indicate that elevated levels of aneuploidy and genomic instability were associated with tumor progression and local recurrence of dysplasia. Conclusions: Mutations in TP53 and MUC5B, as well as deletion of CASP8, may be early driver events in carcinogenesis and could precede the emergence of the APOBEC mutation signature. Moreover, ploidy alterations confer a selective advantage to genomically unstable cells, thereby promoting their progression toward malignant transformation. Collectively, our results demonstrate that genomic instability is prevalent in precancerous lesions and intensifies during the late stages of tumor progression. Cells with a certain level of genomic instability appear to possess a competitive advantage for malignant transformation.

Source: Frontiers in Bioscience-Landmark

DOI: 10.31083/fbl41107