title: Oncosuppressor methylation: a possible key role in colon metastatic progression.
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.
authors.affiliation: Clinical Experimental Oncology Laboratory, National Cancer Centre Giovanni Paolo II, Bari, Italy. s.tommasi@oncologico.bari.it
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Pinto
authors.forename: Daniela
authors.initials: D
authors.lastname: Petriella
authors.forename: Brunella
authors.initials: B
authors.lastname: Pilato
authors.forename: Rosanna
authors.initials: R
authors.lastname: Lacalamita
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Francesco
authors.initials: F
authors.lastname: Zito
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Colucci
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Nicola
authors.initials: N
authors.lastname: Silvestris
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000556:secondary* / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D016000:Cluster Analysis; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000556:secondary* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018168:Receptors, Retinoic Acid / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins