Abstract
CDKN2A is a tumor suppressor gene and is frequently inactivated in human cancers by hypermethylation of its promoter. However, the role and diagnostic value of CDKN2A methylation in esophageal cancer (EC) remains controversial. Therefore, we performed a meta-analysis, including data from 42 articles (2656 ECs, 612 precancerous lesions, and 2367 controls). A significant increase in the frequency of CDKN2A methylation was identified during EC carcinogenesis: cancer vs. controls, odds ratio (OR) = 12.60 (95 % CI, 8.90–17.85); cancer vs. precancerous lesions, OR = 2.89 (95% CI, 2.20–3.79); and precancerous lesions vs. controls, OR = 7.38, 95% (CI, 4.31–12.66). CDKN2A promoter methylation was associated with EC tumor grade (OR = 1.79; 95% CI, 1.20–2.67) and clinical stage (OR = 2.56; 95% CI, 1.33–4.92). Additionally, the sensitivity, specificity, and area under the summary receiver operating characteristic curve (AUC) for diagnosis of EC based on CDKN2A methylation were 0.52 (95% CI, 0.44–0.59), 0.96 (95% CI, 0.93–0.98), and 0.83 (95% CI, 0.79–0.86), respectively. AUCs for blood and tissue sample subgroups were 0.90 and 0.82, respectively. Our findings indicate that CDKN2A methylation has a vital role in EC tumorigenesis and could be a biomarker for early diagnosis of EC.
Highlights
Esophageal cancer (EC) is the eighth most common and the sixth most deadly cancer worldwide [1]
Our results indicated that the frequency of methylation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) promoter was significantly higher in EC cases than in healthy controls (odds ratio (OR) = 12.60, 95 % CI = 8.90–17.85; Figure 2A)
Barrett’s esophagus (BE), a metaplastic condition where the squamous-lined esophageal mucosa is replaced by specialized intestinal mucosa, and dysplasia, are precursor lesions of EC [2, 22]
Summary
Esophageal cancer (EC) is the eighth most common and the sixth most deadly cancer worldwide [1]. Esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) are two major histologic subtypes of EC. EAC is more common in western Europe and north America, whereas ESCC is more prevalent in south-eastern and central Asia, China and Japan [2]. Despite recent advances in combination therapy strategies, including surgery, chemotherapy, and radiotherapy, the prognosis for EC patients remains unsatisfactory, especially for advanced-stage patients, and the 5-year overall survival rate remains at less than 20% [4]. The rapidly increasing incidence, demanding treatment, and poor outcomes of EC highlight the need for effective potential biomarkers for early diagnosis, prognosis prediction, and novel therapeutic targets
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