The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients.
Despite the progress of therapy, outcomes of advanced hepatoblastoma patients who are refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the mortality rate, novel prognostic markers are needed for better therapy planning. We examined the methylation status of 13 candidate tumor suppressor genes in 20 hepatoblastoma tumors by conventional methylation-specific PCR (MSP) and found hypermethylation in 3 of the 13 genes. We analyzed the methylation status of these 3 genes (RASSF1A, SOCS1 and CASP8) in 97 tumors and found hypermethylation in 30.9, 33.0 and 15.5%, respectively. Univariate analysis showed that only the methylation status of RASSF1A but not the other 2 genes predicted the outcome, and multivariate analysis showed a weak contribution of RASSF1A methylation to overall survival. Using quantitative MSP, we found RASSF1A methylation in 44.3% of the 97 tumors. CTNNB1 mutation was detected in 67.0% of the 97 tumors. While univariate analysis demonstrated RASSF1A methylation, CTNNB1 mutation and other clinicopathological variables as prognostic factors, multivariate analysis identified RASSF1A methylation (p = 0.043; relative risk 9.39) and the disease stage (p = 0.002; relative risk 7.67) but not CTNNB1 mutation as independent prognostic factors. In survival analysis of 33 patients in stage 3B or 4, patients with unmethylated tumor had better overall survival than those with methylated tumor (p = 0.035). RASSF1A methylation may be a promising molecular-genetic marker to predict the treatment outcome and may be used to stratify patients when clinical trials are carried out.
Department of Cancer Diagnosis, Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
Shohei
S
Honda
Masayuki
M
Haruta
Waka
W
Sugawara
Fumiaki
F
Sasaki
Miki
M
Ohira
Tadashi
T
Matsunaga
Hiroaki
H
Yamaoka
Hiroshi
H
Horie
Naomi
N
Ohnuma
Akira
A
Nakagawara
Eiso
E
Hiyama
Satoru
S
Todo
Yasuhiko
Y
Kaneko
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers / Q000235:genetics; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D020360:Neoadjuvant Therapy / Q000379:methods; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D005819:Genetic Markers; C411762:RASSF1 protein, human; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C505530:CASP8 protein, human; D053181:Caspase 8