Oncosuppressor methylation: A possible key role in colon metastatic progression

Stefania Tommasi, Rosamaria Pinto, Daniela Petriella, Brunella Pilato, Rosanna Lacalamita, Daniele Santini, Francesco Zito, Giuseppe Colucci, Angelo Paradiso, Nicola Silvestris

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1934-1939
Number of pages6
JournalJournal of Cellular Physiology
Volume226
Issue number7
DOIs
Publication statusPublished - Jul 2011

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Methylation
Colon
Genes
Liver
Tumors
Colorectal Neoplasms
Mutation
Neoplasms
Neoplasm Metastasis
Suppressor Genes
p16 Genes
Biological Therapy
Epigenomics
Carcinogenesis
Tissue

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Oncosuppressor methylation : A possible key role in colon metastatic progression. / Tommasi, Stefania; Pinto, Rosamaria; Petriella, Daniela; Pilato, Brunella; Lacalamita, Rosanna; Santini, Daniele; Zito, Francesco; Colucci, Giuseppe; Paradiso, Angelo; Silvestris, Nicola.

In: Journal of Cellular Physiology, Vol. 226, No. 7, 07.2011, p. 1934-1939.

Research output: Contribution to journalArticle

Tommasi, Stefania ; Pinto, Rosamaria ; Petriella, Daniela ; Pilato, Brunella ; Lacalamita, Rosanna ; Santini, Daniele ; Zito, Francesco ; Colucci, Giuseppe ; Paradiso, Angelo ; Silvestris, Nicola. / Oncosuppressor methylation : A possible key role in colon metastatic progression. In: Journal of Cellular Physiology. 2011 ; Vol. 226, No. 7. pp. 1934-1939.
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abstract = "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.",
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