Prognostic impact of molecular genetic alterations in hepatoblastoma.
BACKGROUND
During recent years, we identified characteristic genetic alterations in sporadic hepatoblastoma (HB). These include loss of heterozygosity (LOH) at the chromosomal region 11p15.5, LOH on chromosome arms 1p and 1q, activating mutations in exon 3 of the beta-catenin gene, as well as overexpression of the c-met oncogene, which encodes the hepatocyte growth factor receptor. We now wanted to evaluate the prognostic relevance of these abnormalities concerning the outcome in a large group of patients.


METHODS
All but 7 of 56 patients with HB were treated either with primary resection for small tumors, or neo-adjuvant chemotherapy with ifosfamide, cisplatin and doxorubicin (IPA) before delayed surgery in case of extended disease and additional adjuvant IPA therapy in all cases. Seven tumors were primarily resected and adjuvantly treated with different cytotoxic drugs. LOH 11p15.5, LOH 1p, and LOH 1q were detected in tumor tissue in comparison to normal liver and/or peripheral blood leukocytes by PCR based microsatellite analysis. Beta-catenin mutations were analysed with SSCP, deletion screening and direct sequencing. RT-PCR was used for identification of c-met mRNA overexpression. The results were correlated with the tumors' stage, histological type and epithelial differentiation, as well as with the patients' outcome.


RESULTS
Overall disease-free survival after median follow-up of 5 years was 43/56 patients (77%). LOH 11p15.5 was found in 15/56, LOH1p in 11/53, LOH1q in 7/53 and beta-catenin mutations in 25/55 HB. 13/23 HB had a c-met overexpression. LOH 11p15.5 and LOH 1p were significantly more often found in embryonal HB, while there was no correlation of other genetic alterations with histological type or differentiation. Furthermore, statistical analysis revealed no correlation of any of these disorders with initial tumor stage, nor with the patients' outcome.


CONCLUSIONS
None of the investigated molecular genetic alterations are suited to serve as a prognostic indicator in HB. Further investigations, especially genetic screening of tumor tissue may reveal prognostic markers for this neoplasm.
von Schweinitz
Dietrich
D
Department of Pediatric Surgery, University of Basle Childrens' Hospital, Basle, Switzerland. Dietrich.vonSchweinitz@unibas.ch
Kraus
Jürgen A
JA
Albrecht
Steffen
S
Koch
Arend
A
Fuchs
Jörg
J
Pietsch
Torsten
T
D002648:Child; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D005819:Genetic Markers; D005858:Germany / Q000453:epidemiology; D018197:Hepatoblastoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D019656:Loss of Heterozygosity; D009154:Mutation; D011379:Prognosis; D015534:Trans-Activators; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; D015534:Trans-Activators; D051176:beta Catenin