[en] AIMS: Activation of β-catenin has been identified as a possible mechanism for the development of nephroblastomas. In our study we investigated whether this activation occurs already in precursor lesions of nephroblastomas, called nephrogenic rests (NRs). Inactivation of the adenomatous polyposis coli (APC) protein is an important regulatory mechanism of activating β-catenin. We clarified the role of APC by assessing loss of heterozygosity (LOH) and possible mutations within the genomic region.
METHODS: Activation of β-catenin was examined by immunohistochemistry identifying nuclear translocation. Two polymorphic loci of the APC gene were investigated for LOH and sequence analysis was performed for the mutation cluster region of the APC gene on formalin fixed, paraffin embedded samples.
RESULTS: Four of the 18 nephroblastomas available for immunohistochemistry exhibited nuclear staining of β-catenin, but none of the NRs. Analysis of LOH revealed 14 homozygous samples, 10 heterozygous tumours and six tumours exhibiting LOH of the APC gene. One blastema-type nephroblastoma showed nuclear localisation of β-catenin in conjunction with LOH of the APC gene. Analysis of 12 nephroblastomas revealed no sequence aberration.
CONCLUSION: Our results indicate that nuclear activation of β-catenin is a late event in the tumorigenesis of nephroblastomas coinciding in some tumours with LOH of the APC gene.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Grill, Christine ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling ; Department of Pathology General Hospital and Paracelsus Medical University Salzburg, Salzburg
Sunitsch, Sandra; Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria ; Institute of Forensic Medicine, Medical University of Graz, Graz, Austria
Hatz, Martina; Center for Medical Research, Medical University of Graz, Graz, Austria
Hauser-Kronberger, Cornelia
Leuschner, Ivo; Kiel Pediatric Tumor Registry, Department of Paediatric Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany
Hoefler, Gerald; Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria
Guertl, Barbara; Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria
Language :
English
Title :
Activation of beta-catenin is a late event in the pathogenesis of nephroblastomas and rarely correlated with genetic changes of the APC gene.
Murphy WM, Grignon DJ, Perlman EJ. Kidney tumors in children. In: Murphy WM, Grignon DJ, Perlman EJ, editors. Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington DC: Armed Forces Institute of Pathology, 2004; 1-100.
Beckwith BJ. Prescursor lesions of Wilms tumor: clinical and biological implications. Med Pediatr Oncol 1993; 21: 158-68.
Beckwith BJ, Kiviat NB, Bonadio JF. Nephrogenic rests, nephroblastoma-tosis and the pathogenesis of Wilms' tumor. Pediatr Pathol 1990; 10: 1-36. ́ (Pubitemid 20130951)
Hennigar RA, OShea PA, Grattan-Smith JD. Clinicopathologic features of nephrogenicrestsandnephroblastomatosis.AdvAnatPathol2001;8:276-89.
Coppes MJ, Arnold M, Beckwith JB, et al. Factors affecting the risk of contralateral Wilms tumor development: a report from the National Wilms Tumor Study Group. Cancer 1999; 85: 1616-25. (Pubitemid 29152837)
Bergeron C, Iliescu C, Thiesse P, et al. Does nephroblastomatosis influence the natural history and relapse rate in Wilms tumour? A single center experience over 11 years. Eur J Cancer 2001; 37: 385-91. (Pubitemid 32182328)
Mossimann C, Hausmannand G, Basler K. b-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev 2009; 10: 276-86.
Koesters R, Niggli F, vonKnebel M, et al. Nuclear accumulation of b-catenin protein in Wilms' tumours. J Pathol 2003; 199: 68-76. (Pubitemid 36054731)
Li CM, Kim CE, Margolin AA, et al. CTNNB1 mutations and over-expression of Wnt/b-catenin target genes in WT1-mutant Wilms' tumors. Am J Pathol 2004; 165: 1943-53. (Pubitemid 39578373)
Ramburan A, Oladiran F, Smith C, et al. Microsatellite analysis of the adenomatous polyposis (APC) gene and immunoexpression of b catenin in nephroblastomas: a study including 83 cases treated with preoperative chemotherapy. J Clin Pathol 2005; 58: 44-50. (Pubitemid 40070495)
Fuzukawa R, Heathcott RW, Moore HE. Sequential WT1 and CTNNB1 mutations and alterations of beta-catenin localisation in intralobar nephro-genic rests and associated Wilms tumours: two case studies. J Clin Pathol 2007; 60: 1013-6. (Pubitemid 47441934)
Willert K, Jones KA. Wnt signaling: is the party in the nucleus? Genes Dev 2006; 20: 1394-404. (Pubitemid 43830647)
Major MB, Camp ND, Berndt JD, et al. Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. Science 2008; 316: 988-99.
Giles RH, vanEs JH, Clevers H. Caught up in a Wnt storm: Wnt signalling in cancer. Biochim Biophys Acta 2003; 1653: 1-24. (Pubitemid 36627817)
Guertl B, Ratschek M, Harms D, et al. Clonality and loss of heterozygosity of WT genes are early events in the pathogenesis of nephroblastomas. Hum Pathol 2003; 34: 278-81. (Pubitemid 36356681)
Kraus C, Ballhausen WG. Two intragenic polymorphisms of the APC-gene detected by PCR and enzymatic digestion. Hum Genet 1991; 88: 705-6.
Guertl B, Beham A, Zechner R, et al. Nasopharyngeal angiofibroma: an APC-gene-associated tumor? Hum Pathol 2000; 31: 1411-3.
Davies SM, Snover DC. Frequent polymorphism in exon 15 of the adenomatous polyposis coli gene. Hum Genet 1994; 93: 329-30. (Pubitemid 24066937)
Corbin M, Reynies A, Rickman DS, et al. WNT/b-catenin pathway activation in Wilms tumors: a unifying mechanism with multiple entries? Genes Chromosomes Cancer 2009; 48: 816-27.
Yaoita E, Sato N, Yoshida Y, et al. Cadherin and catenin staining in podocytes in development and puromycin aminonucleoside nephrosis. Nephrol Dial Transplant 2002; 17: 16-9.
Fukuzawa R, Heathcott RW, Sano M, et al. Myogenesis inWilms' tumor is associated with mutations of the WT1 gene and activation of bcl2 and the Wnt signaling pathway. Ped Dev Pathol 2004; 7: 125-37. (Pubitemid 38715332)
Kim MA, Lee HS, Lee HE, et al. Prognostic importance of epithelial-mesenchymal transition-related protein expression in gastric carcinoma. Histopathol 2009; 54: 442-51.
Onder TT, Gupta PB, Mani SA, et al. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 2008; 68: 3645-54.
Schmidt-Ott KM, Barasch J. Wnt/b-catenin signaling in nephron progenitors and their epithelial progeny. Kidney Int 2008; 74: 1004-8.
Seo JO, Han SI, Lim SC. Role of CDK8 and beta-catenin in colorectal adenocarcinoma. Oncol Rep 2010; 24: 285-91.
Kurihara S, Oda Y, Ohishi Y, et al. Coincident expression of beta-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas. Mod Pathol 2010; 23: 225-34.
