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Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma
Author(s) -
Sugawara Waka,
Haruta Masayuki,
Sasaki Fumiaki,
Watanabe Naoki,
Tsunematsu Yukiko,
Kikuta Atsushi,
Kaneko Yasuhiko
Publication year - 2007
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.21031
Subject(s) - hepatoblastoma , methylation , dna methylation , medicine , oncology , univariate analysis , epigenetics , stage (stratigraphy) , cancer research , gastroenterology , gene , multivariate analysis , biology , genetics , gene expression , paleontology
Background Despite the progress of therapy, about 25% of patients with hepatoblastoma succumb to the disease. Prognostic factors, as well as improved therapies, are needed for these patients. We investigated the incidence and clinical significance of genetic and epigenetic aberrations in hepatoblastoma. Procedure β ‐ catenin mutation was analyzed by sequencing and promoter hypermethylation of the RASSF1A and SFRP genes by methylation‐specific PCR after bisulfate treatment of DNA samples from 39 hepatoblastomas. Association of the clinical and biological features, including sex, age of patients, stage of the disease, the histological type, and the β ‐ catenin and RASSF1A status with overall survival was evaluated using univariate and multivariate analysis. Results β ‐ catenin mutation and RASSF1A methylation were found in 22 (56.4%) and 15 (38.5%) of 39 hepatoblastomas, respectively, but SFRP s methylation was not found in any of them. RASSF1A and SFRP s were unmethylated in five adjacent normal liver tissues. Patients with a RASSF1A methylated tumor were older in age (≥2 years, P = 0.036), at more advanced stages ( P = 0.009), and had more frequent β‐catenin mutation ( P < 0.001) and poorer outcome ( P < 0.001) than those with a RASSF1A unmethylated tumor. While univariate analysis showed the prognostic significance of age, stage, the histological type, and the β‐catenin and RASSF1A status, multivariate analysis showed only the RASSF1A methylation status as an independent factor predicting outcome (relative risk, 10.51; 95% CI, 1.21 ∼ 90.97; P = 0.033). Conclusions RASSF1A methylation may be a novel molecular‐genetic marker for treatment outcome in hepatoblastoma if confirmed by studies examining a larger number of hepatoblastomas. Pediatr Blood Cancer. Pediatr Blood Cancer 2007;49:240–249. © 2006 Wiley‐Liss, Inc.