PTEN Phosphohydrolase; PTEN protein, human; Base Sequence; Child; Humans; Kidney Neoplasms/genetics; Kidney Neoplasms/pathology; Loss of Heterozygosity; Molecular Sequence Data; PTEN Phosphohydrolase/genetics; Wilms Tumor/genetics; Wilms Tumor/pathology; Nephroblastoma; Nephrogenic rest; PTEN; Pathology and Forensic Medicine
Abstract :
[en] Recent genetic investigations of nephroblastomas point to an activation of the Wnt pathway. Data indicate however that activation might be partly due to cross talk of different signaling pathways including the tumor suppressor gene PTEN (phosphatase and tensin homolog on chromosome 10). Therefore, we examined expression and chromosomal aberrations of PTEN in nephroblastomas of different subtypes and the corresponding nephrogenic rests. Loss of heterozygosity was analyzed by high-resolution melting analysis of 4 different single nucleotide polymorphisms. Results were confirmed by sequence analysis of the polymerase chain reaction products. In addition, an intragenic insertion-deletion polymorphism of the PTEN gene was investigated. Protein expression was assessed by immunohistochemistry. Twenty-two nephroblastomas and their corresponding nephrogenic rests were included in the study. In the high-resolution melting analysis, 15 samples were homozygous, 6 were heterozygous, and for 1 sample results could not be obtained for technical reasons. None of the samples showed loss of heterozygosity. Nineteen of the tumors and corresponding nephrogenic rests were also examined immunohistochemically. All tumors showed cytoplasmic positivity, with the exception of 1 tumor that showed complete loss of staining. In 1 tumor, the epithelial component showed distinct cytoplasmic staining, whereas the immature muscle and hyaline cartilage were negative. All nephrogenic rests exhibited positive cytoplasmic staining of all components. Our results establish that inactivation of PTEN is a rare and late event in the pathogenesis of nephroblastomas.
Disciplines :
Urology & nephrology
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, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria
Guelly, Christian; Centre of Medical Research, Medical University of Graz, A-8010 Graz, Austria
Ebner, Birgit; Centre of Medical Research, Medical University of Graz, A-8010 Graz, Austria
Leuschner, Ivo; Kiel Pediatric Tumor Registry, Institute of Pathology, Christian Albrechts University Kiel, D-24105 Kiel, Germany
Hauser-Kronberger, Cornelia; Department of Pathology General Hospital, Paracelsus Medical University Salzburg Muellner, A-5020 Salzburg, Austria
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 :
Loss of PTEN/MMAC1 activity is a rare and late event in the pathogenesis of nephroblastomas.
This project was partly funded by the Thyssen Stiftung (Koeln, Germany), project number AZ.20.06.0.046, and the Salzburger Krebshilfe (Salzburg, Austria) (nonprofit organizations).
Murphy WM, Grignon DJ, Perlman EJ. Kidney tumors in children. In: Murphy WM, et al, editor. Tumors of the kidney, bladder, and related urinary structures. Washington USA: Armed Forces Institute of Pathology; 2004. p. 1-100.
Beckwith B.J. Prescursor lesions of Wilms tumor: clinical and biological implications Med Pediatr Oncol 21 1993 158 168
Beckwith J.B., Kiviat N.B., and Bonadio J.F. Nephrogenic rests, nephroblastomatosis and the pathogenesis of Wilms' tumor Pediatr Pathol 10 1990 1 36
Hennigar R.A., O'Shea P.A., and Grattan-Smith J.D. Clinicopathologic features of nephrogenic rests and nephroblastomatosis Adv Anat Pathol 8 2001 276 289
Coppes M.J., Arnold M., and Beckwith J.B. Factors affecting the risk of contralateral Wilms tumor development: a report from the National Wilms Tumor Study Group Cancer 85 1999 1616 1625
Bergeron C., Iliescu C., and Thiesse P. Does nephroblastomatosis influence the natural history and relapse rate in Wilms' tumour? A single center experience over 11 years Eur J Cancer 37 2001 385 391
Maehama T., and Dixon J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol3,4,5- triphosphate J Biol Chem 273 1998 13375 13378
Brenner W., Färber G., and Herget T. Loss of tumor suppressor protein PTEN during renal carcinogenesis Int J Cancer 99 2002 53 57
Hara S., Oya M., and Mizuno R. Akt activation in renal cell carcinoma: contribution of decreased PTEN expression and the induction of apoptosis by an Akt inhibitor Ann Oncol 16 2005 928 933
Sükösd F., Digon B., and Fischer J. Allelic loss at 10q23.3 but lack of mutation of PTEN/MMAC1 in chromophobe renal cell carcinoma Cancer Genet Cytogenet 128 2001 161 163
Hing S., Lu Y.J., and Summersgill B. Gain of 1q is associated with adverse outcome in favorable histology Wilms' tumors Am J Pathol 158 2001 393 398
Guertl B., Ratschek M., and Harms D. Clonality and loss of heterozygosity of WT genes are early events in the pathogenesis of nephroblastomas Hum Pathol 34 2003 278 281
Fukuzawa R., Anaka M.R., and Heathcott R.W. Wilms tumour histology is determined by distinct types of precursor lesions and not epigenetic changes J Pathol 215 2008 377 387
Fuzukawa R., Anaka M.R., and Weeks R.J. Canonical WNT signalling determines lineage specificity in Wilms tumour Oncogene 28 2009 1063 1075
Koesters R., Niggli F., and vonKnebel Doeberitz M. Nuclear accumulation of β-catenin protein in Wilms' tumours J Pathol 199 2003 68 76
Corbin M., Reynies A., and Rickman D.S. WNT/β-catenin pathway activation in Wilms tumors: a unifying mechanism with multiple entries? Genes Chromosomes Cancer 48 2009 816 827
Maschietto M., deCamargo B., and Brentani H. Molecular profiling of isolated histological components of Wilms tumor implicates a common role for the Wnt signaling pathway in kidney and tumor development Oncology 75 2008 81 91
Huang M., Wang Y., and Sun D. Identification of genes regulated by Wnt/β-catenin pathway and involved in apoptosis via microarray analysis BMC Cancer 6 2006 221
Persad S., Troussard A.A., and McPhee T.R. Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation J Cell Biol 153 2001 1161 1174
Ford-Hutchinson A.F., Ali Z., and Lines S.E. Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth J Bone Miner Res 22 2007 1245 1259
Surawan A., Escobar J., and Frank J.W. Developmental regulation of the activation of signaling components leading to translation initiation in skeletal muscle of neonatal pigs Am J Physiol Endocrinol Metab 91 2006 E849 E859
VanNederveen F.H., Perren A., and Dannenberg H. PTEN gene loss, but not mutation in benign and malignant phaechromocytomas J Pathol 209 2006 274 280
Sansal I., and Sellers W.R. The biology and clinical relevance of the PTEN tumor suppressor pathway J Clin Oncol 22 2004 2954 2963
