title: Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates.
abstract: Hepatoblastoma (HB) is very rare but the most common malignant neoplasm of the liver occurring in children. Despite improvements in therapy, outcomes for patients with advanced HB that is refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the survival rate among this group, identification of novel prognostic markers and therapeutic targets is needed. We have previously reported that altered DNA methylation patterns are of biological and clinical importance in HB. In the present study, using genome-wide methylation analysis and bisulfite pyrosequencing with specimens from HB tumors, we detected nine methylated genes. We then focused on four of those genes, GPR180, MST1R, OCIAD2, and PARP6, because they likely encode tumor suppressors and their increase of methylation was associated with a poor prognosis. The methylation status of the four genes was also associated with age at diagnosis, and significant association with the presence of metastatic tumors was seen in three of the four genes. Multivariate analysis revealed that the presence of metastatic tumors and increase of methylation of GPR180 were independent prognostic factors affecting event-free survival. These findings indicate that the four novel tumor suppressor candidates are potentially useful molecular markers predictive of a poor outcome in HB patients, which may serve as the basis for improved therapeutic strategies when clinical trials are carried out.
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Honda
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Minato
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujiyoshi
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Miyagi
authors.affiliation: Department of Cancer Diagnosis, Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haruta
authors.affiliation: Department of Cancer Diagnosis, Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Kanako C
authors.initials: KC
authors.lastname: Hatanaka
authors.affiliation: Japanese Study Group for Pediatric Liver Tumor, Hiroshima, Japan.
authors.forename: Eiso
authors.initials: E
authors.lastname: Hiyama
authors.affiliation: Department of Cancer Diagnosis, Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kamijo
authors.affiliation: Faculty of Education, School Health Nursing, Hokkaido University of Education, Sapporo, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Taketomi
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics; D000328:Adult; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D016147:Genes, Tumor Suppressor; D015894:Genome, Human / Q000235:genetics; D018197:Hepatoblastoma / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D017422:Sequence Analysis, DNA; D013447:Sulfites
chemical_list: C478763:GPR180 protein, human; D009363:Neoplasm Proteins; C576226:OCIAD2 protein, human; D043562:Receptors, G-Protein-Coupled; D013447:Sulfites; D036002:ADP Ribose Transferases; C579799:PARP6 protein, human; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C042345:hydrogen sulfite
keywords: Hepatoblastoma; methylation; prognostic marker; survival; tumor suppressor