Abstract
Background and aim
Aberrant methylation of Ras association domain family 1, isoform A (RASSF1A), and short-stature homeobox gene 2 (SHOX2) promoters has been validated as a pair of valuable biomarkers for diagnosing early lung adenocarcinomas (LUADs). Epidermal growth factor receptor (EGFR) is the key driver mutation in lung carcinogenesis. This study aimed to investigate the aberrant promoter methylation of RASSF1A and SHOX2, and the genetic mutation of EGFR in 258 specimens of early LUADs.
Methods
We retrospectively selected 258 paraffin-embedded samples of pulmonary nodules measuring 2 cm or less in diameter and evaluated the diagnostic performance of individual biomarker assays and multiple panels between noninvasive (group 1) and invasive lesions (groups 2A and 2B). Then, we investigated the interaction between genetic and epigenetic alterations.
Results
The degree of RASSF1A and SHOX2 promoter methylation and EGFR mutation was significantly higher in invasive lesions than in noninvasive lesions. The three biomarkers distinguished between noninvasive and invasive lesions with reliable sensitivity and specificity: 60.9% sensitivity [95% confidence interval (CI) 52.41–68.78] and 80.0% specificity (95% CI 72.14–86.07). The novel panel biomarkers could further discriminate among three invasive pathological subtypes (area under the curve value > 0.6). The distribution of RASSF1A methylation and EGFR mutation was considerably exclusive in early LUAD (P = 0.002).
Conclusion
DNA methylation of RASSF1A and SHOX2 is a pair of promising biomarkers, which may be used in combination with other driver alterations, such as EGFR mutation, to support the differential diagnosis of LUADs, especially for stage I.
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Data availability
The data utilized and analyzed in this study are available upon reasonable request to the corresponding author. Detailed data that might endanger participant consent and confidentiality are not published.
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Acknowledgements
The authors thank the pathology department of The Nanfang Hospital of Southern Medical University for providing excellent technical support for this study.
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Jie Lin conceived and provided the research ideas for this paper. Xiangyu Ji collected samples and performed data analysis and wrote the original manuscript. Hong Li and Hui-Hui Chen are responsible for performing the experiments and evaluating the results. Xiangyu Ji# and Hong Li# contributed equally to this work and share first authorship. All authors read and approved the final manuscript.
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Ji, XY., Li, H., Chen, HH. et al. Diagnostic performance of RASSF1A and SHOX2 methylation combined with EGFR mutations for differentiation between small pulmonary nodules. J Cancer Res Clin Oncol 149, 8557–8571 (2023). https://doi.org/10.1007/s00432-023-04745-8
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DOI: https://doi.org/10.1007/s00432-023-04745-8