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bioRxiv · 10.1101/2025.09.11.675674

Integrated Expression Analysis of C-MYC Oncogene-Associated Pathways in Gastric Adenocarcinoma and its Correlation with Clinicopathological Factors

Guimaraes, K. S. A. P.·Marinho, M. F. P.·Nwoye, J. S.·Mourao, R. M. D. S.·Pinto, J. B. A.·da Silva, J. M. C.·Pereira, D.·Santos da Silva, V. C.·Demachki, S.·Barra, W. F.·Moreira, F.·Burbano, R. R.·Assumpcao, P. P.
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Abstract

BackgroundThe C-MYC oncogene is a well-established driver of gastric carcinogenesis, yet the integrated expression pattern of its complex regulatory network and its clinical implications in gastric adenocarcinoma (GAC) remain to be fully elucidated. This study aimed to perform an integrated bioinformatic analysis of C-MYC and its associated pathways in a cohort of GAC patients to delineate its expression profile, assess its potential as a biomarker, and correlate its patterns with clinicopathological factors such as Lauren classification and neoadjuvant treatment status. MethodsThe study included transcriptome data from 74 GAC tumor samples and 68 normal gastric tissue samples. Following RNA sequencing, a comprehensive bioinformatic analysis was conducted on a curated list of 21 C-MYC-associated genes. The methodology included differential expression analysis (DESeq2), unsupervised hierarchical clustering, Principal Component Analysis (PCA), and Receiver Operating Characteristic (ROC) curve analysis to evaluate diagnostic performance. Gene expression levels were also statistically correlated with Lauren histological subtypes and neoadjuvant therapy status using the Wilcoxon rank-sum test. ResultsThe analysis revealed a profound dysregulation of the C-MYC network in GAC. While MYC itself was significantly upregulated, its transcriptional antagonists, particularly MXD4 and MXD3, were the most significantly downregulated genes. This gene signature robustly separated tumor from normal tissues in both hierarchical clustering and PCA. ROC analysis demonstrated the outstanding diagnostic potential of several genes, with MXD4 achieving a perfect Area Under the Curve (AUC) of 1.00, surpassing the diagnostic value of MYC (AUC=0.86). Stratification by Lauren classification showed that MYC and its stability regulator PTBP1 were significantly more expressed in the intestinal subtype, whereas the repressors MXD3 and MXI1 were higher in the diffuse subtype. No significant expression differences were observed based on neoadjuvant treatment status. ConclusionGastric adenocarcinoma is characterized by a coordinated dysregulation of the C-MYC network, marked by both oncogene activation and a concurrent loss of its key transcriptional repressors. The profound downregulation of antagonists like MXD4 serves as an exceptionally accurate molecular signature for GAC, suggesting its potential as a diagnostic biomarker superior to MYC alone. The divergent expression patterns between Lauren subtypes highlight distinct molecular pathobiology and may have implications for targeted therapies

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Guimaraes, K. S. A. P., Marinho, M. F. P., Nwoye, J. S., Mourao, R. M. D. S., Pinto, J. B. A., da Silva, J. M. C., Pereira, D., Santos da Silva, V. C., Demachki, S., Barra, W. F., Moreira, F., Burbano, R. R., Assumpcao, P. P.. 2025-09-16. Integrated Expression Analysis of C-MYC Oncogene-Associated Pathways in Gastric Adenocarcinoma and its Correlation with Clinicopathological Factors. https://doi.org/10.1101/2025.09.11.675674

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