S. Tommasi and R. Pinto equally contributed to this work.
Original Research Article
Oncosuppressor methylation: A possible key role in colon metastatic progression
Article first published online: 19 APR 2011
Copyright © 2010 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 226, Issue 7, pages 1934–1939, July 2011
How to Cite
Tommasi, S., Pinto, R., Petriella, D., Pilato, B., Lacalamita, R., Santini, D., Zito, F., Colucci, G., Paradiso, A. and Silvestris, N. (2011), Oncosuppressor methylation: A possible key role in colon metastatic progression. J. Cell. Physiol., 226: 1934–1939. doi: 10.1002/jcp.22524
- Issue published online: 19 APR 2011
- Article first published online: 19 APR 2011
- Accepted manuscript online: 10 NOV 2010 12:00AM EST
- Manuscript Accepted: 27 OCT 2010
- Manuscript Received: 8 JUL 2010
K-RAS and BRAF gene mutations are mandatory to set anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients. Due to the relationship of these mutations with tumor epigenotype, we hypothesized the potential role of oncosuppressor methylation of genes involved in K-RAS/BRAF pathway (CDKN2A, RASSF1A, and RARbeta suppressor genes) in inhibiting EGFR signaling cascade. Primary tumor and synchronous liver metastatic tissues of 75 mCRC patients were characterized for promoter methylation by QMSP and for K-RAS and BRAF mutations. RARbeta, RASSF1A, and CDKN2A genes were methylated in 82%, 35%, and 26% of primary tumors, respectively. RASSF1A resulted significantly more frequently methylated in liver metastasis than in primary site (P = 0.015), while RARbeta was significantly lower methylated in distant metastasis (P = 1.2 × 10−6). As regards methylation content, RASSF1A methylation status was significantly higher in liver metastasis with respect to primary tumor (P = 0.000) underlying the role of this gene in liver metastatic progression. In our series K-RAS and BRAF were mutated in 39% and 4% of cases, respectively. Methylation frequencies seemed to be unrelated to gene mutations; on the other hand, RASSF1A mean content methylation resulted significantly higher in liver than in primary tumor (288.78 vs. 56.23, respectively, P = 0.05) only in K-RAS wild-type cases sustaining a specific role of this gene in metastatic site thus supporting its function in strengthening the apoptotic role of K-RAS. These evidences held the role of oncosuppressor methylation in both colon tumorigenesis and progression and suggested that epigenetic events should be taken into account when biological therapies in mCRC patients have to be set. J. Cell. Physiol. 226: 1934–1939, 2011. © 2010 Wiley-Liss, Inc.