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Mutations of the P53 Tumor Suppressor Gene Occur Infrequently in Wilms' Tumor' David Malkin,2 Elizabeth Sexsmith, Herman Yeger, Bryan It G

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Mutations of the P53 Tumor Suppressor Gene Occur Infrequently in Wilms' Tumor' David Malkin,2 Elizabeth Sexsmith, Herman Yeger, Bryan It G [CANCER RESEARCH54, 2077-2079, April 15, 1994] Advances in Brief Mutations of the p53 Tumor Suppressor Gene Occur Infrequently in Wilms' Tumor' David Malkin,2 Elizabeth Sexsmith, Herman Yeger, Bryan it G. Williams, and Max J. Coppes Division of Hematology/Oncology, Department of Pediatrics fD. M., E. S.], and Department of Pathology [H. }‘j,The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Cancer Biology, Research Institute, The Cleveland Clinic Foundation@ Cleveland Ohio 44195 [B. R. G. WJ; and the Pediatric Oncology Program, Alberta Children's Hospita4 Calgary, Alberta, Canada T2T 5C7 (M. J. C.] Abstract ample, nephrogenic rests, foci of persistent embryonal nonmalignant remnants, are demonstrated within the kidneys of approximately 30— Mutations of the p53 tumor suppressor gene occur frequently in a 40% of children with WI' (14). These lesions are apparent precursors variety ofadult-onset tumors, including colon, breast, lung, and brain, yet of WT (15). Wi' is also associated with specific congenital abnormal are infrequently identified In pediatric malignancies. Wilma' tumor, a common solid tumor ofchildhood, can be associated with mutations of the ities, including genitourinary anomalies, sporadic aniridia, mental w'ri gene.Alterationsofthep53genehavebeenshownto modulatethe retardation, and hemihypertrophy (16). Genetic predisposition to WT ability of WT1 to transactivate its targets. Although positive p5.3 immu is recognized in two distinct syndromes with urogenital malforma nostaining has been demonstrated in Wilms' tumors, the correlation to tions (WAGR syndrome and Denys-Drash syndrome), as well as in p53 genemutations is not clear. We examinedWilms' tumor samplesfor BWS, a congenital overgrowth syndrome characterized by growth p53 mutatIons utilizing polymerasechain reaction-single-strandconfor abnormalities and a predisposition to several embryonal neoplasms, mation polymorphism analysis and single-strand DNA sequencing. Muta including Wi' (16). These congenital defects have been linked with dons in the coding region of the p5.3 gene were demonstrated in 2 of 21 specific genetic loci implicated in Wilms' tumorigenesis. They in (9.5%) Wilms' tumors. Each mutation yielded a substitution ofamino acid dude the WAGR locus at chromosome 1lpl3 and the BWS locus at residues. One mutation was located in exon 6 and the other in exon 7. Both mutations were found in tumors from patients with advanced stage dis chromosome lipiS. The WAGR locus encompasses several contigu ease. Focal anaplasia was demonstrated in one of these tumors. Our data ous genes, including the Wilms' tumor suppressor gene W7'l, while suggest that although p53 mutatIons occur infrequently In Wilma' tumor, the BWS locus includes the gene implicated in BWS as well as a they may be associated with advanced disease. putative second Wilms tumor suppressor gene, W72 (reviewed in Refs. 17—19). Introduction Although alterations of p53 have not been implicated in Wilms' tumorigenesis, recent observations by Maheswaran et a!. (20) have The p53 tumor suppressor gene is located on the short arm of demonstrated that p53 can physically interact with WTJ in transfected human chromosome 17 and encodes a 53-kDa nuclear phosphoprotein cells and that this interaction modulates the ability of each protein to that appears to act as a negative regulator of cell proliferation (1, 2). transactivate their respective targets. The association of these two The protein probably achieves its function by blocking the progres factors is also implicated by the rare occurrence of Wilms' tumors in sion of cells through the cell cycle late in G1 (3). In addition, p53 some Li-Fraumeni families who carry constitutional alterations of the seems to act as a transcription activator that suppresses abnormal cell p53 gene, predisposing affected members to cancer (21). We set out proliferation by acting as a G1 cell cycle checkpoint control for DNA to determine the frequency of p53 alterations in an unselected series damage (4). Alterations of the p53 gene and its encoded protein are of Wilms' tumors of varying histological subtypes and stage. the most frequently encountered genetic events in human cancer, Genomic DNA extracted from Wilms' tumor samples were screened having been reported in almost every type of sporadic neoplasm (5, 6). using PCR and SSCP as described previously (22). Those samples that Few studies, however, have reported the frequency ofp53 alterations showed altered electrophoretic mobility compared to the wild-type in tumors of pediatric origin. Missense mutations of p53 in neuro controls by SSCP were sequenced to further characterize the specific blastoma (7, 8), neuroblastoma cell lines (9), rhabdomyosarcoma (10), mutations. These results are discussed in the context of the histopatho rhabdomyosarcoma cell lines (10), Ewing's sarcoma (9), and pediatric logical features of the tumor, as well as clinical characteristics of the acute lymphoblastic leukemia (11) have been demonstrated in a small patient. number of studies. WT,3 or nephroblastoma, is an embryonal malignancy that arises Materials and Methods from remnants of immature kidney. It affects approximately 1 in 10,000 children, usually before the age of 6 years (median age at Thirty-two consecutive diagnostic Wilms tumor specimens were obtained diagnosis, 3.5 years) (12). Approximately 5—10%of children are (21 at pretreatment biopsy, 11 at resection postchemotherapy), immediately affected bilaterally, either at presentation (synchronous bilateral Wi') snap-frozen in liquid nitrogen, and then stored at —70°C.Beforeprocessing for or with unilateral disease initially, followed by the development of a DNA analysis, the tumor tissue was ground to a fme powder under liquid contralateral tumor (asynchronous or metachronous bilateral WT) nitrogen. Age at diagnosis, sex, tumor histopathology (favorable histology versus anaplastic), clinical stage according to the National Wilms' Tumor (13). Wi' is often associated with certain peculiar features. For cx Study (23), and clinical outcome were documented and recorded for each patient sample. Genomic DNA that had been isolated and stored previously Received 12/28/93; accepted 3/4/94. using standard procedures was resuspended in 10 mr@iTris-1mMEDTA, pH The costs of publication of this article were defrayed in part by the payment of page 8.0, to a concentration of 50 ng/pJ. Inadequate quality or quantity of DNA charges. This article must therefore be hereby marked advertisement in accordance with 18U.S.C.Section1734solelyto indicatethisfact. precluded 6 samples from being analyzed, while five additional samples were 1 This work was supported by the Medical Research Council of Canada. excludedbecauseof incompleteclinical data. 2 To whom requests for reprints should be addressed, at Division of Oncology, The PCR:SSCP and Sequencing Analysis. Twenty-one W'F samples were Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. available for analysis (14 were diagnostic samples, 7 were postchemotherapy). 3 The abbreviations used are: WT, Wilma' tumor; BWS, Beckwith-Wiedemann syn drome;PCR, polymerasechain reaction;SSCP, single-strandconformationalpolymor Nine sets of primers were generated to amplify DNA fragments spanning phism; WAGR, Wilms'-aniridia-genitourinary anomalies. exons 2 and 4 through 11 of the p53 gene. These primers have been published 2077 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1994 American Association for Cancer Research. p53 IN WILMS' TUMOR previously (22, 24). PCR was performed using 100—500ng of template DNA mutationsTwoTable2 Characteristicsofsomaticp.5.3 in 50 mMTris-HC1 (jH 8.6) with 1.5 mM MgCI2,0.2 mMconcentrations of aneutralbase-pairalterationswere identifiedin Wit-34. One at codon 213 represents each deoxynucleotide triphosphate, 250 ng of each primer, 1 pAof [32P]dC'FP polymorphism.Sample (3000 Ci/mmol) diluted 1:10, and 2.5 units of Taq polymerase (AmpliTaq; switchWit-34Exon Codon Sequencechange Aminoacid Cetus) in a 50-pA total reaction volume. The reaction conditions for the Gly-'ArgWit-346 199 OOA-'AGA Perkin-Elmer 480 thermocycler were: 94°C(45 s); 55°C(45 s); and 72°C(45 Arg—*ArgWit-286 213 CGA—@GGA s) for 35 cycles. The reaction was initiated with one 10-mm incubation at 85°C 7 257 CFG-@CAG Leu—*Gln and terminated with a 7-min incubation at 72°Cfollowedby 3 mm at 94°C.An equal volume of the PCR product was added to a loading buffer (95% formamide, 20 mM EDTA, 0.05% bromophenol blue, and 0.05% xylene samples. Repeated sequence analysis of 3 of these failed to identify cyanol). The samples were denaturedat 85°Cfor5 mm and loaded immedi base-pair alterations. However, two Wilms' tumor samples (Wit-28 ately onto an acrylamide-tris buffered EDTA nondenaturing gel. The gels and Wit-34) demonstrated abnormal band-shift patterns on SSCP contained 4.5—9.0%acrylamideand 2—10%glycerol,depending on the exon analysis that were subsequently confirmed to represent abnormalities fragment being analyzed. Electrophoresis was performed at 25 W for 6 to 7 h of the nucleotide sequence. In the exon 6 fragment of sample Wit-34, or 10 W for 15—17hat room temperature. The gel was dried and exposed to a transition from A to 0 in the third position of codon 213 was X-OMAT film (Kodak) with an intensifying screen at —70°Cfor4 to 72 h. Each fragment was run under two or three electrophoretic conditions, again identified. This base substitution does not change the amino acid depending on the specific fragment being analyzed. Each gel carried both encoded (arginine) and thus represents either a polymorphism (26) or positive and negative controls, to be sure that known mutations could consis silent mutation. However, this sample also contains a true mutation in tently be appreciated. DNA samples determined to be abnormal by detectable exon 6 as represented by a base-pair substitution from G to A in the band shifts on SSCP were reamplified with the SSCP primers encompassing first position of codon 199 yielding an amino acid change from the abnormal region. Fragments were subcloned directly into a T-tailed pBSK glycine to arginine.
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