Furthermore thirteen tumours harbouring mutations/deletions also showed Y654 β-catenin

expression in the cytoplasm. Further studies must be carried out to ascertain the effect of mutated β-catenin on the nuclear accumulation of the c-Met related β-catenin pool. Overall analysis of tumours with aberrant β-catenin expression revealed only a small percentage (5%) that has neither mutations in the CTNNB1 gene nor expression of tyrosine654-phosphorylated β-catenin (Figure 6). These tumours may have mutations in other genes such as AXIN or APC Ganetespib that lead to abnormal β-catenin accumulation or activation through a different pathway. These findings underline that aberrant activation of β-catenin may be critical to the pathogenesis of HB but the means of this activation may not be as important as was previously thought. Figure 6 HB samples with aberrant β-catenin expression showing the breakdown of samples with gene mutations/deletions and Y654-β-catenin protein expression. Our finding of a large number of tumours (79%) with c-Met SHP099 in vivo activated β-catenin may be relevant to treatment of HB. Although treatment

with cisplatin or PLADO followed by resection is highly successful there remains > 15% of HB that suffer from relapse. These relapse patients are often refractive to conventional chemotherapy and have a survival rate of < 20%. The translation of our findings may be important for design of future clinical trials, identifying patients for individual targeted therapy, allowing for fewer side effects or inclusion of c-Met inhibitors in salvage therapy following relapse. Our findings may also have an application in the treatment of other tumours that display ®-catenin activation without associated gene mutation. Somatic mutations in exon 3 of the ®-catenin gene have been reported in a variety of cancers (16, 32). However, aberrant accumulation of ®-catenin without activating mutations has been reported Lepirudin in cancers such as gastrointestinal carcinoid tumour, ovarian cancer, cutaneous

lymphoma, malignant melanoma and pancreatic adenocarcinoma [41–46]. HGF/c-Met activation of ®-catenin may account for the Fedratinib supplier discrepancies between gene mutation and protein expression seen in these tumours and this could indicate susceptibility to RTK-targeting agents in the treatment regimen. Disclosure of Potential Conflicts of interests The authors declare that they have no competing interests. Acknowledgements The authors wish to acknowledge Dr Lucia Alonso-Gonzalez and Dr Tracy Hale for their comments on the manuscript. This work has been supported by the Robert McCelland Trust, the Canterbury Medical Research Foundation, the Child Cancer Foundation and the Children’s Cancer Research Trust. The authors wish to acknowledge the SIOPEL Liver tumour strategy group and all participating centres, particularly those contributing tumours material for this study. References 1. Perilongo G, et al.: SIOPEL trials using preoperative chemotherapy in hepatoblastoma.