p53 and mdm-2 Expression in Rhabdomyosarcoma of Childhood and Adolescence: Clinicopathologic Study by the Kiel Pediatric Tumor Registry and the German Cooperative Soft Tissue Sarcoma Study
Available accessResearch articleFirst published online March, 2003
p53 and mdm-2 Expression in Rhabdomyosarcoma of Childhood and Adolescence: Clinicopathologic Study by the Kiel Pediatric Tumor Registry and the German Cooperative Soft Tissue Sarcoma Study
Rhabdomyosarcomas (RMS) are the most common malignant soft tissue sarcomas in childhood and adolescence. Despite a large number of publications about this heterogeneous group of tumors, little is known about proliferation, p53 and mdm-2 in relation to histological subtype, clinical parameter, and prognosis of patients. We studied 150 cases of RMS treated in the German Cooperative Soft Tissue Sarcoma Study (CWS) by immunohistochemistry on paraffin-embedded tissue, using antibodies against p53, mdm-2, and Ki-67. The results were correlated with histological subtype, mitotic count, and various clinical parameters. Both p53 and mdm-2 were expressed at low levels and did not show differences between embryonal and alveolar RMS. Tumors of patients with metastatic embryonal RMS showed significantly higher levels of p53 protein than nonmetastatic tumors. This might be a clue to an important role of p53 in metastatic embryonal RMS. Nevertheless, neither p53 nor mdm-2 showed any correlation to prognosis. Proliferation measured by Ki-67 immunostaining (KiS5 antibody) or mitotic count did not show significant differences between embryonal and alveolar RMS. In addition, these parameters did not correlate with response to therapy or prognosis. In conclusion, we could not demonstrate that any of the investigated parameters had an influence on prognosis of RMS. p53 protein over-expression might be a crucial step in metastatic disease for patients with embryonal RMS.
CroceCM, IsobeM, EmanuelBS, GivolD, OrenM.Localization of gene for human p53 tumour antigen to band 17p13. Nature1986;320:84–85.
2.
LinzerDI, LevineAJ. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell1979;17:43–52.
3.
NigroJM, BakerSJ, PreisingerAC, Mutations in the p53 gene occur in diverse human tumour types. Nature1989;342:705–708.
4.
HollsteinM, SidranskyD, VogelsteinB, HarrisCC. p53 mutations in human cancers. Science1991;253:49–53.
5.
Resnick-SilvermanL, St. ClairS, MaurerM, ZhaoK, ManfrediJJ. Identification of a novel class of genomic DNA-binding sites suggests a mechanism for selectivity in target gene activation by the tumor suppressor protein p53. Genes Dev1998;12:2102–2107.
6.
FerreiraCG, TolisC, GiacconeG.p53 and chemosensitivity. Ann Oncol1999;10:1011–1021.
7.
WürlP, MeyeA, SchmidtH, High prognostic significance of mdm2/p53 co-overexpression in soft tissue sarcomas of the extremities. Oncogene1998;16:1183–1185.
8.
YooJ, LeeHK, KangCS, ParkWS, LeeJY, ShimSI. p53 gene mutations and p53 expression in human soft tissue sarcomas. Arch Pathol Lab Med1997;121:395–399.
9.
KawaiA, NoguchiM, BeppuY, Nuclear immunoreaction of p53 protein in soft tissue sarcomas. Cancer1994;73:2499–2505.
10.
MulliganLM, MatlashewskiGJ, ScrableHJ, CaveneeWK. Mechanisms of p53 loss in human sarcomas. Proc Natl Acad Sci USA1990;87:5863–5867.
11.
WürlP, TaubertH, BacheM, Frequent occurrence of p53 mutations in rhabdomyosarcoma and leiomyosarcoma, but not in fibrosarcoma and malignant neural tumors (Abstract). Int J Cancer1996;69:317–323.
12.
KusafukaT, FukuzawaM, OueT, KomotoY, YonedaA, OkadaA.Mutation analysis of p53 gene in childhood malignant solid tumors. J Pediatr Surg1997;32:1175–1180.
13.
DillerL, SexsmithE, GottliebA, LiFP, MalkinD.Germ-line p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest1995;95:1606–1611.
14.
FelixCA, KappelCC, MitsudomiT, Frequency and diversity of p53 mutations in childhood rhabdomyosarcoma. Cancer Res1992;52:2243–2247.
15.
BirchJM, HartleyAL, TrickerKJ, Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res1994;54:1298–1304.
16.
AyanI, DoganÖ, KebudiR, Immunohistochemical detection of p53 protein in rhabdomyosarcoma: association with clinicopathological features and outcome. J Pediatr Hematol Oncol1997;19:48–53.
17.
MomandJ, WuHH, DasguptaG.mdm2—master regulator of the p53 tumor suppressor protein. Gene2000;242:15–29.
WaberPG, ChenJ, NisenPD. Infrequency of mdm2 gene amplification in pediatric solid tumors and lack of association with p53 mutations in adult squamous cell carcinomas. Cancer Res1993;53:6028–6030.
20.
DrobnjakM, LatresE, PollackD, Prognostic implications of p53 nuclear overexpression and high proliferation index in adult soft-tissue sarcomas. J Natl Cancer Inst1994;86:549–554.
21.
HiltonDA, LoveS, BarberR.Demonstration of apoptotic cells in tissue sections by in situ hybridization using digoxigenin-labeled poly(A) oligonucleotide probes to detect thymidine-rich DNA sequences. J Histochem Cytochem1997;45:13–20.
NewtonWAJr., GehanEA, WebberBL, Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification. An Inter-group Rhabdomyosarcoma Study. Cancer1995;76:1073–1085.
24.
HsuSM, RaineL, FangerHJ. Use of avidin-biotin peroxidase complex (ABC) in immunoperoxidase technique: a comparison between ABC and unlabeled antibody PAP procedures. Histochem Cytochem1981;29:577–580.
25.
HsuSM, SobanE.Color modification of diaminobenzidine (DAB) precipitation by metallic ions and its application for double immunohistochemistry. J Histochem Cytochem1982;30:1079–1082.
26.
NortonAJ, JordanS, YeomanP.Brief, high-temperature heat denaturation (pressure cooking): a simple and effective method of antigen retrieval for routinely processed tissues. J Pathol1994;173:371–379.
27.
RodaryC, FlamantF, DonaldsonSS. An attempt to use a common staging system in rhabdomyosarcoma: a report of an international workshop initiated by the International Society of Pediatric Oncology (SIOP). Med Pediatr Oncol1989;17:210–215.
28.
MaurerHM, BeltangadyM, GehanEA, The Inter-group Rhabdomyosarcoma Study—I. A final report. Cancer1988;61:209–220.
29.
de AlavaE, AntonescuCR, PanzioA, Prognostic impact of p53 status in Ewing sarcoma. Cancer2000;89:783–792.
Di LeonardiA, LinkeSP, ClarkinK, WahlGM. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev1994;8:2540–2551.
32.
KeletiJ, QuezadoMM, AbazaMM, RaffeldM, TsokosM.The mdm2 oncoprotein is overexpressed in rhabdomyosarcoma cell lines and stabilizes wild-type p53 protein. Am J Pathol1996;149:143–151.
33.
BomanF, BrelD, AntunesL, AlhamanyZ, FloquetJ, Boccon-GibodL.Gene alterations and apoptosis in rhabdomyosarcoma. Pediatr Pathol Lab Med1997;17:233–247.
34.
HarmsD.Alveolar rhabdomyosarcoma: a prognostically unfavorable rhabdomyosarcoma type and its necessary distinction from embryonal rhabdomyosarcoma. In: HarmsD, SchmidtD, eds. Current Topics in Pathology, vol. 89: Soft Tissue Tumors. Berlin: Springer-Verlag, 1995:273–296.
35.
KoscielniakE, HarmsD, HenzeG, Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol1999;17:3706–3719.
36.
YapDBS, HsiehJK, ChanFSG, LuX.mdm2: a bridge over the two tumour suppressors, p53 and Rb. Oncogene1999;18:7681–7689.
37.
MeddebM, ValentA, DanglotG, MDM2 amplification in a primary alveolar rhabdomyosarcoma displaying a t(2;13)(q35;q14). Cytogenet Cell Genet1996;73:325–330.
38.
JensenV, BrandtSorensen F, BentzenSM, Proliferative activity (MIB-1 index) is an independent prognostic parameter in patients with high-grade soft tissue sarcomas of subtypes other than malignant fibrous histiocytomas: a retrospective immunohistochemical study including 216 soft tissue sarcomas. Histopathology1998;32:536–546.
39.
ChoongPF, AkermanM, WillenH, Prognostic value of Ki-67 expression in 182 soft tissue sarcomas. Proliferation—a marker of metastasis? APMIS1994;102:915–924.
40.
JensenV, HoyerM, SorensenFB, KellerJ, JensenOM. MIB-1 expression and iododeoxyuridine labelling in soft tissue sarcomas: an immunohistochemical study including correlations with p53, bcl-2 and histological characteristics. Histopathology1996;28:437–444.
41.
PindzolaJA, PalazzoJP, KovatichAJ, TumaB, NobelM.Expression of p21 WAF1/CIP1 in soft tissue sarcomas: a comparative immunohistochemical study with p53 and Ki-67. Pathol Res Pract1998;194:685–691.
42.
KreipeH, WackerHH, HeidebrechtHJ, Determination of the growth fraction in non-Hodgkin's lymphomas by monoclonal antibody Ki-S5 directed against a formalin-resistant epitope of the Ki-67 antigen. Am J Pathol1993;142:1689–1694.
43.
HeidebrechtHJ, BuckF, HaasK, WackerHH, ParwareschR.Monoclonal antibodies Ki-S3 and Ki-S5 yield new data on the ‘Ki-67’ proteins. Cell Prolif1996;29:413–425.
