the Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne
    United Kingdom Children's Cancer Study Group, University of Leicester, Leicester
    Department of Radiotherapy, Cookridge Hospital, Leeds, United Kingdom

    ABSTRACT

    PURPOSE: Identifying pathobiological correlates of clinical behavior or therapeutic response currently represents a key challenge for medulloblastoma research. Nuclear accumulation of the ?-catenin protein is associated with activation of the Wnt/Wg signaling pathway, and mutations affecting components of this pathway have been reported in approximately 15% of sporadic medulloblastomas. We tested the hypothesis that nuclear immunoreactivity for ?-catenin is a prognostic marker in medulloblastoma, and assessed the relationship between nuclear ?-catenin immunoreactivity and mutations of CTNNB1 and APC.

    PATIENTS AND METHODS: Medulloblastomas from children entered onto the International Society for Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group (UKCCSG) PNET3 trial (n = 109) were examined for ?-catenin immunoreactivity, and where tissue was available, evidence of CTNNB1 and APC mutations. The results were correlated with clinicopathologic variables, principally outcome.

    RESULTS: Children with medulloblastomas that showed a nucleopositive ?-catenin immunophenotype (27 of 109; 25%) had significantly better overall (OS) and event-free (EFS) survivals than children with tumors that showed either membranous/cytoplasmic ?-catenin immunoreactivity or no immunoreactivity (P = .0015 and P = .0026, respectively). For ?-catenin nucleopositive and nucleonegative medulloblastomas, 5-year OS was 92.3% (95% CI, 82% to 100%) versus 65.3% (95% CI, 54.8 to 75.7%), and 5-year EFS was 88.9% (95% CI, 77% to 100%) versus 59.5% (95% CI, 48.8 to 70.2%), respectively. Mutations in CTNNB1 were found exclusively among medulloblastomas that demonstrated nuclear ?-catenin immunoreactivity, but no evidence of APC mutation was found in these cases. All children with ?-catenin nucleopositive large cell/anaplastic medulloblastomas and ?-catenin nucleopositive medulloblastomas presenting with metastatic disease are alive at least 5 years postdiagnosis.

    CONCLUSION: Nuclear accumulation of ?-catenin appears to be a marker of favorable outcome in medulloblastoma, and should be investigated further in large group-wide trials.

    INTRODUCTION

    Advances in treatment regimens for medulloblastoma, an embryonal neuroepithelial tumor of the cerebellum and the most common malignant CNS tumor in children, have improved 5-year survival rates for standard-risk patients to approximately 70%. However, many surviving children have long-term cognitive and/or neuroendocrine adverse effects, and survival rates for high-risk patients are as low as 25%.1,2 Currently, the two principal scientific challenges presented by medulloblastomas are: (1) identifying pathobiologic correlates of its heterogeneous behavior to facilitate therapeutic stratification and reduce adverse treatment effects, and (2) finding novel therapies for those children with biologically aggressive tumors.3

    One approach to disease stratification is to combine histopathologic evaluation with an assessment of molecular abnormalities associated with biologic behavior or therapeutic response.4 The occurrence of medulloblastoma in type 2 Turcot's syndrome, in which patients have multiple colonic polyps and germline mutations in the APC tumor suppressor gene, has suggested that abnormalities of the Wnt/Wingless (Wnt/Wg) pathway could be involved in the development of sporadic medulloblastomas.5,6 Subsequently, mutations in components of the Wnt/Wg pathway, including APC and CTNNB1 (encoding ?-catenin), have been consistently demonstrated in approximately 15% of sporadic medulloblastomas and are predicted to cause aberrant pathway activation.7-10

    The critical downstream effector of the canonical Wnt/Wg pathway is ?-catenin.6 Cytoplasmic ?-catenin is regulated by a multimeric protein complex, which contains the APC, GSK-3?, and AXIN proteins. In the "pathway-inactive" state, GSK-3? phosphorylates ?-catenin, signaling it for degradation through the ubiquitin-proteasome system. Pathway activation destabilizes the protein complex, upregulating levels of ?-catenin and enhancing its translocation to the nucleus. Here, it acts as a coactivator of Tcf/Lef transcription factors, which regulate genes involved in cell cycle progression, apoptosis, and differentiation. Thus, nuclear accumulation of ?-catenin is a marker for physiologic or abnormal Wnt/Wg pathway activation.

    The purpose of this study of medulloblastomas was twofold: (1) to test the hypothesis that nuclear accumulation of ?-catenin is a prognostic marker, and (2) to evaluate any association between ?-catenin status and the presence of APC and CTNNB1 mutations.

    PATIENTS AND METHODS

    Clinicopathologic Details

    Medulloblastomas (n = 109) from children registered on the International Society for Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group (UKCCSG) PNET3 trial protocol were provided by several SIOP/UKCCSG centers.11-13 Cohort size was determined by tissue availability. Of this study's cohort, 71 children had been part of the randomized trial described previously,11 the remainder having been treated according to protocol. Tumors were classified histopathologically as classic (n = 89; 82%) or large cell/anaplastic (n = 20; 18%) variants.14,15 Poor recruitment of desmoplastic tumors (n = 5) precluded the inclusion of this variant in the study. Clinical data, including current status, were available from the UKCCSG data center. Median age at diagnosis was 8.3 years (range, 3.0 to 16.8 years), and there was a prevalence of males (1.6:1). Overall, a greater proportion of patients (60%) had received radiotherapy/chemotherapy than radiotherapy alone.11 Median survival was 7.5 years. Metastatic disease at presentation was demonstrated by central radiologic review of 14 patients (all Chang stage M3), all of which were part of a previously described series of 68 patients with M2-3 disease.13

    Immunohistochemistry

    Immunohistochemistry was undertaken on 5-μm sections of formalin-fixed paraffin wax-embedded (FFPE) tumors, using a microwave antigen retrieval step carried out in 0.01M citrate buffer (pH 6.0) for 10 minutes. A primary antibody to ?-catenin (BD Transduction Laboratories, San Jose, CA) was applied at a concentration of 1:100. Antigen-antibody complexes were revealed using a biotinylated antimouse IgG second stage and a Vectastain ABC Elite Kit (Vector Laboratories, Burlingame, CA) with diaminobenzidine as the chromogen. A section containing a colonic carcinoma and adjacent normal colonic epithelium was used as a control.

    Mutational Analysis of CTNNB1 and APC by Direct DNA Sequencing

    Genomic DNA was extracted from FFPE tumors using a DNeasy tissue kit (Qiagen, Crawley, UK), according to manufacturer's instructions. Polymerase chain reaction (PCR) products spanning (1) the GSK-3? phosphorylation domain of ?-catenin (nucleotides 791-1070, Genbank accession number X89579; Invitrogen, Paisley, UK), and (2) the mutation cluster region of APC (nucleotides 3784-4627, Genbank accession number NM000038; Invitrogen, Paisley, UK) were generated using specific PCR primers and standard PCR conditions (Invitrogen, Paisley, UK; available at http://www.ncl.ac.uk/nicr/research/ebtd/paed/Ellison_et_al_primers.pdf). PCR products were sequenced on forward and reverse strands using a CEQ DTCS kit, and analyzed on a CEQ 2000XL DNA analysis system (both Beckman Coulter, Fullerton, CA). All mutations detected were confirmed by independent replicate analysis.

    Statistical Methods

    Survival curves were produced and log-rank tests performed to compare overall survival (OS) and event-free survival (EFS) in accordance with various potential prognostic indicators. OS was defined as the time between date of diagnosis and date of death. EFS was defined as the time between date of diagnosis and date of first event, which was recurrence or death from any cause. Patients still alive at the end of the study were censored at the date of last follow-up. CIs for OS and EFS were calculated using Greenwood's formula. All observed prognostic variables were tested individually in a Cox proportional hazards model using the change in log likelihood from the null model.16 Those shown to be significant (P < .05) were entered into a multivariate model in a stepwise procedure taking a P value of .05 to enter and .05 to be removed.17 The final analysis was performed in January 2005.

    RESULTS

    ?-Catenin Immunohistochemistry

    There were two principal patterns of ?-catenin immunoreactivity in medulloblastoma cells; cytoplasmic staining and combined cytoplasmic/nuclear staining (Fig 1). ?-catenin immunoreactivity of the cytoplasmic membrane alone characterized a proportion of cells in some tumors. A few medulloblastomas were devoid of ?-catenin immunoreactivity, but most showed at least focal labeling. Combined cytoplasmic/nuclear ?-catenin staining tended to characterize sheets or groups of cells, rather than scattered single cells, and could be categorized as strong/widespread or moderate/patchy. Overall, nuclear ?-catenin immunoreactivity, indicative of Wnt/Wg pathway activation, was detected in 27 (25%) of 109 medulloblastomas, being strong in 11 of 27 and moderate in 16 of 27 of the tumors.

    Mutational Analysis of CTNNB1 and APC

    Tissue was available for mutational analysis of CTNNB1 and APC in 15 of 27 medulloblastomas with a nuclear ?-catenin immunophenotype (Fig 1). A CTNNB1 missense point mutation was identified in 9 (60%) of 15 of these tumors: codon 32 GAC>TAC; ASP>TYR (3 cases), codon 32 GAC>AAC; ASP>ASN, codon 32 GAC>TAC; ASP>VAL, codon 33 TCT>TAT; SER>TYR, codon 34 GGA>GAA; GLY>GLU, codon 37 TCT>TAT; SER>TYR and codon 37 TCT>TGT; SER>CYS (each in one case). APC mutations were not found in ?-catenin nucleopositive medulloblastomas. Of the nine tumors with CTNNB1 mutations, four demonstrated strong and five demonstrated moderate ?-catenin immunoreactivity. CTNNB1 mutations were not detected in ?-catenin nucleonegative tumors, for which tissue was available (n = 33).

    Clinicopathologic Correlates of ?-Catenin Status

    There was a significant association between ?-catenin immunoreactivity and outcome, both in terms of OS (P = .0015; Fig 2A) and EFS (P = .0026; Fig 2B). Patients with ?-catenin nucleopositive medulloblastomas had much better OS and EFS compared with those with nucleonegative tumors; 5-year OS 92.3% (95% CI, 82% to 100%) versus 65.3% (95% CI, 54.8 to 75.7%) respectively, and 5-year EFS 88.9% (95% CI, 77% to 100%) versus 59.5% (95% CI, 48.8 to 70.2%), respectively. Only three of 27 children who developed a medulloblastoma with a nuclear ?-catenin immunophenotype have relapsed. One of these three children is alive, 9 years postdiagnosis, and two have died, with overall survival times of 4.8 years and 5.1 years. Neither of these two children had metastatic disease at presentation, and the tumors from both were classic variants showing moderate nuclear ?-catenin immunoreactivity. CTNNB1 was wild type in one, but there was a CTNNB1 mutation (ASP32TYR) in the other. The remaining 24 children are alive without disease, having a median follow-up period of 7.6 years (range, 4.2 to 11.1 years). There was no significant association between ?-catenin status and either age or sex.

    Children with large cell/anaplastic (LC/A) medulloblastomas had a significantly poorer outcome than those with classic tumors, both in terms of OS (P = .021) and EFS (P = .016). Five-year overall survival for children with classic and LC/A tumors was 76.9% (95% CI, 67.9 to 85.8%) versus 50% (95% CI, 28.1 to 71.9%), respectively. ?-catenin nucleopositivity occurred among classic and LC/A tumors with frequencies of 26% and 20%, respectively. Of the 27 medulloblastomas with nuclear ?-catenin immunoreactivity, four (15%) were LC/A variants. There was no clear relationship between cytologic anaplasia and ?-catenin immunophenotype in regions of these four tumors; however, some anaplastic foci did demonstrate nuclear accumulation of ?-catenin. The four children with ?-catenin nucleopositive LC/A tumors are still alive, 5 to 10.7 years postdiagnosis.

    Central radiologic review revealed metastatic disease at presentation in 14 of 109 children. Moderate ?-catenin nucleopositivity was present in tumors from three of these 14 children, all of whom are still alive 7.5 to 10.8 years postdiagnosis. In contrast, of the 11 of 14 children with ?-catenin nucleonegative medulloblastomas and metastatic disease at presentation, only three are still alive.

    Repeating the survival analyses after excluding patients with metastatic disease from the cohort made no difference to the significance of any results. Those children with ?-catenin nucleopositive medulloblastomas (n = 24) had a significantly better outcome than those children (n = 71) with ?-catenin nucleonegative tumors (5-year OS, 91.3%; 95% CI, 79.7% to 100% v 68.3%; 95% CI, 57.2% to 79.3%, respectively; P = .009; 5-year EFS, 87.5%; 95% CI, 74.2% to 100% v 63%; 95% CI, 51.7% to 74.3%, respectively; P = .016), and patients with classic medulloblastomas (n = 76) had a significantly better outcome than those patients (n = 19) with LC/A tumors (5-year OS, 79.4%; 95% CI, 70% to 88.7% v 52.6%; 95% CI, 30.2% to 75.1%, respectively; P = .018; 5-year EFS, 74.7%; 95% CI, 64.9% to 84.6% v 47.4%; 95% CI, 24.9% to 69.8%, respectively; P = .014).

    Several clinicopathologic variables, including those found previously to be of prognostic significance in SIOP/UKCCSG PNET3 trial patients, were entered into Cox proportional hazards models for OS and EFS (Tables 1 and 2, respectively). ?-catenin nuclear immunoreactivity and pathologic variant were independent prognostic indicators for both OS and EFS, whereas time to complete radiotherapy was an independent prognostic indicator for EFS. Metastatic disease was excluded as a variable from these analyses because there were too few patients (n = 14). However, when the analyses were repeated for the cohort minus patients with metastatic disease (n = 95), alterations to hazard ratios and P values were minimal and insignificant (data not shown).

    DISCUSSION

    Our study is the first to show a significant association between nuclear ?-catenin immunoreactivity and a favorable outcome in a large uniformly treated cohort of children with nondesmoplastic medulloblastomas. This finding might be unexpected, given ?-catenin's role in promoting proliferation among neuronal progenitors and data from studies of colonic, lung, and hepatocellular carcinomas indicating that ?-catenin immunoreactivity is associated with both enhanced cell proliferation and an aggressive behavior.18-21 However, the downstream effects of Wnt/Wg pathway activation are multifarious and tissue specific; activation can promote apoptosis and/or growth arrest in various cell systems.22-25 Also, Wnt/Wg pathway activation in medulloblastomas may be idiosyncratic, affecting the balance between cell proliferation and cell death to produce tumor cells that are prone to apoptotic stimuli or particularly radiosensitive. At its simplest, pathologic activation of the Wnt/Wg pathway in medulloblastomas could be one element of an associated set of molecular abnormalities that select for a variant with a less aggressive phenotype. In this respect, it may be pertinent that activation of the Wnt/Wg pathway in transgenic mice has not generated tumors.26

    Our study was undertaken on tumors from a subset of children enrolled onto the SIOP/UKCCSG PNET3 trial.11-13 Clinical and pathologic indices for this subset closely match those of the original trial cohort.11,12,15 In addition, the results of our univariate and multivariate survival analyses mirror those for the original trial cohort, with only one exception; EFS was significantly different for each treatment arm in the original trial cohort, but not in the current study.11,12 There was a trend toward improved EFS with preradiotherapy chemotherapy if patients with metastatic disease were excluded from our study's cohort (5-year EFS, 74.7%; 95% CI, 62.7% to 86.6%, for preradiotherapy chemotherapy v 64.3%; 95% CI, 49.8% to 78.8%, respectively; P = .31). However, we have shown that the principal findings of this study are unaltered by the inclusion or exclusion, in the analyzed cohort, of patients that present with metastatic disease.

    Because ?-catenin immunoreactivity can be assessed alongside tumor histopathology in FFPE tissue, its utility as a potential prognostic marker in medulloblastoma is greater than those markers that can be assayed only in freshly frozen tissue. However, its integration into refined classification schemes incorporating histopathologic and molecular evaluation will depend on whether it is an independent marker of biologic behavior or therapeutic response. Our data suggest that this is the case. We also noted that children with ?-catenin nucleopositive tumors in combination with metastatic disease at presentation or LC/A histopathology did not have the expected poor outcome. There were three children with metastatic disease and a ?-catenin nucleopositive tumor. All three children have survived 7.5 to 10.8 years postdiagnosis. Furthermore, all the children with ?-catenin nucleopositive LC/A medulloblastomas have survived 5 to 10.7 years postdiagnosis.

    We have previously analyzed about half of the current series of tumors for loss of chromosome 17p and MYCC/MYCN amplification, which are cytogenetic markers of a poor prognosis in medulloblastoma.27 Of the tumors in this cohort showing ?-catenin nucleopositivity, none showed loss of 17p or MYCN amplification, and only one demonstrated MYCC amplification. This medulloblastoma combined MYCC amplification in 20% of its cells with moderate/patchy nuclear ?-catenin immunoreactivity, and was notable for affecting one of only two children who died as a result of a ?-catenin–nucleopositive tumor. The full molecular data set for these 60 medulloblastomas is available online (http://www.ncl.ac.uk/nicr/research/ebtd/paed/Ellison_et_al.htm). Overall, our data indicate that ?-catenin immunoreactivity is likely to be a valuable marker in histopathologic/molecular classifications of medulloblastoma; ?-catenin nucleopositive medulloblastomas are uncommonly associated with clinicopathologic or molecular markers of an adverse prognosis, and when they are, prolonged survival is possible. Among proposed molecular markers of outcome in medulloblastoma, only ?-catenin nuclear immunoreactivity and TrkC overexpression have been associated with a good outcome,4,28 offering the potential for stratifying patients into therapeutic regimens that produce less long-term cognitive adverse effects.

    Our results indicate that missense point mutations affecting the GSK-3? phosphorylation domain of CTNNB1 are associated with aberrant nuclear accumulation of ?-catenin in about two thirds of medulloblastomas. All detected mutations alter critical residues, in which mutations have been described in other cancers, and would be predicted to impair ?-catenin phosphorylation and degradation, leading to its nuclear accumulation.6 APC mutations were not associated with ?-catenin nuclear accumulation in our series. Only missense point mutations of APC have been observed in medulloblastoma,9,10 in contrast with the inactivating deletions and truncating mutations that are commonly observed in other cancers and result in Wnt/Wg pathway activation.29 Together, these results suggest that the APC mutations observed in medulloblastoma do not play a significant role in Wnt/Wg pathway activation, but may exert any functional effects through alternative mechanisms.

    Although we cannot exclude the involvement of mutations outside the GSK-3? phosphorylation domain of CTNNB1 or the mutation cluster region of APC, Wnt/Wg pathway activation in medulloblastoma appears to result from alternative mechanisms to CTNNB1 or APC mutation in a significant proportion (40%) of cases. Alternative tumor-specific mechanisms of pathway activation have been reported, including upregulation of the Akt oncogene, overexpression of Pin1, and mutation or inactivation of the AXIN1, SIAH1, and SFRP family of candidate tumor suppressor genes.30-34 The potential role of these in pathway activation now requires investigation in medulloblastoma.

    In conclusion, ?-catenin nuclear immunoreactivity appears to be a marker of good prognosis in medulloblastoma. Its utility should now be tested alongside other clinicopathologic and molecular prognostic indicators, such as histopathologic variant, loss of chromosome 17p, MYC amplification, and TrkC overexpression, in biologic studies attached to the SIOP/UKCCSG PNET4 trial and similar trials elsewhere.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Acknowledgment

    Thanks are due to Andrew Brown and Janet Thompson, of the Department of Neuropathology, Newcastle General Hospital, for technical assistance, and to Kath Robinson at the UKCCSG data center. The collaboration of staff in all centers across Europe that contributed to the SIOP PNET3 trial is gratefully acknowledged.

    NOTES

    Supported by Grants from the Samantha Dickson Research Trust and the Faculty of Medical Sciences, University of Newcastle. The United Kingdom Children's Cancer Study Group is supported by Cancer Research UK.

    This research was approved by the Newcastle and North Tyneside Local Research Ethics Committee and by the Biological Studies Committee of the United Kingdom Children's Cancer Study Group.

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

    REFERENCES

    Mulhern RK, Merchant TE, Gajjar A, et al: Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 5:399-408, 2004

    Rood BR, Macdonald TJ, Packer RJ: Current treatment of medulloblastoma: Recent advances and future challenges. Semin Oncol 31:666-675, 2004

    Ellison DW, Clifford SC, Gajjar A, et al: What's new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol 7:53-66, 2003

    Ellison DW: Classifying the medulloblastoma: Insights from morphology and molecular genetics. Neuropathol Appl Neurobiol 28:257-282, 2002

    Gilbertson RJ: Medulloblastoma: Signalling a change in treatment. Lancet Oncol 5:209-218, 2004

    Kikuchi A: Tumor formation by genetic mutations in the components of the Wnt signaling pathway. Cancer Sci 94:225-229, 2003

    Baeza N, Masuoka J, Kleihues P, et al: AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene 22:632-636, 2003

    Eberhart CG, Tihan T, Burger PC: Nuclear localization and mutation of beta-catenin in medulloblastomas. J Neuropathol Exp Neurol 59:333-337, 2000

    Huang H, Mahler-Araujo BM, Sankila A, et al: APC mutations in sporadic medulloblastomas. Am J Pathol 156:433-437, 2000

    Koch A, Waha A, Tonn JC, et al: Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 93:445-449, 2001

    Taylor RE, Bailey CC, Robinson K, et al: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study. J Clin Oncol 21:1581-1591, 2003

    Taylor RE, Bailey CC, Robinson KJ, et al: Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma. Int J Radiat Oncol Biol Phys 58:1184-1193, 2004

    Taylor RE, Bailey CC, Robinson KJ, et al: Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 41:727-734, 2005

    Eberhart CG, Burger PC: Anaplasia and grading in medulloblastomas. Brain Pathol 13:376-385, 2003

    McManamy CS, Lamont JM, Taylor RE, et al: Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62:627-632, 2003

    Parmar MKB, Machin D: Survival Analysis: A Practical Approach. Chichester, United Kingdom, J Wiley & Sons, 1995

    Collett D: Modelling Survival Data in Medical Research. London, United Kingdom, Chapman & Hall, 1996

    Bondi J, Bukholm G, Nesland JM, et al: Expression of non-membranous beta-catenin and gamma-catenin, c-Myc and cyclin D1 in relation to patient outcome in human colon adenocarcinomas. Apmis 112:49-56, 2004

    Kotsinas A, Evangelou K, Zacharatos P, et al: Proliferation, but not apoptosis, is associated with distinct beta-catenin expression patterns in non-small-cell lung carcinomas: Relationship with adenomatous polyposis coli and G(1)-to S-phase cell-cycle regulators. Am J Pathol 161:1619-1634, 2002

    Nhieu JT, Renard CA, Wei Y, et al: Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol 155:703-710, 1999

    Zechner D, Fujita Y, Hulsken J, et al: Beta-catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev Biol 258:406-418, 2003

    Damalas A, Kahan S, Shtutman M, et al: Deregulated beta-catenin induces a p53- and ARF-dependent growth arrest and cooperates with Ras in transformation. EMBO J 20:4912-4922, 2001

    Kim K, Pang KM, Evans M, et al: Overexpression of beta-catenin induces apoptosis independent of its transactivation function with LEF-1 or the involvement of major G1 cell cycle regulators. Mol Biol Cell 11:3509-3523, 2000

    Olmeda D, Castel S, Vilaro S, et al: Beta-catenin regulation during the cell cycle: Implications in G2/M and apoptosis. Mol Biol Cell 14:2844-2860, 2003

    Wang J, Wynshaw-Boris A: The canonical Wnt pathway in early mammalian embryogenesis and stem cell maintenance/differentiation. Curr Opin Genet Dev 14:533-539, 2004

    Kratz JE, Stearns D, Huso DL, et al: Expression of stabilized beta-catenin in differentiated neurons of transgenic mice does not result in tumor formation. BMC Cancer 2:33, 2002

    Lamont JM, McManamy CS, Pearson AD, et al: Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 10:5482-5493, 2004

    Grotzer MA, Janss AJ, Fung K, et al: TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18:1027-1035, 2000

    Fearnhead NS, Britton MP, Bodmer WF: The ABC of APC. Hum Mol Genet 10:721-733, 2001

    Iwai A, Marusawa H, Matsuzawa S, et al: Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates beta-catenin activity in a p53-dependent manner. Oncogene 23:7593-7600, 2004

    Pang R, Yuen J, Yuen MF, et al: PIN1 overexpression and beta-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma. Oncogene 23:4182-4186, 2004

    Satoh S, Daigo Y, Furukawa Y, et al: AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24:245-250, 2000

    Sharma M, Chuang WW, Sun Z: Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation. J Biol Chem 277:30935-30941, 2002

    Suzuki H, Watkins DN, Jair KW, et al: Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417-422, 2004

查询更多Childhood相关信息在本站>>

《临床肿瘤学医学期刊》2005年11月第23卷第11期