Abstract
Purpose
The P53–MDM2 pathway plays a central role in sarcoma pathogenesis. Functional P53 Arg72Pro and MDM2 T309G single-nucleotide polymorphisms (SNP) are considered to have significant effects on risk of sarcomas.
Methods
Several molecular epidemiology studies have evaluated how these genetic variants are involved in sarcoma development, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically examine the association between these functional SNPs and sarcoma risk.
Results
There are four studies eligible for P53 Arg72Pro SNP (466 sarcoma patients and 552 controls), and three studies for MDM2 T309G SNP (355 sarcoma patients and 645 controls). Pooled odds ratios were appropriately calculated using either fixed-effect model or random-effect model. We did not find a significant association between P53 Arg72Pro polymorphism and sarcoma risk. However, in a stratified analysis, a statistically significant correlation between this SNP and osteosarcoma risk was observed. For MDM2 T309G variant, pooled results from the meta-analysis indicate that carriers of TG and GG genotypes showed a 34% increased risk to develop sarcomas compared to TT carriers.
Conclusion
These results suggest that the functional MDM2 T309G genetic variant may play a more important role in carcinogenesis of sarcoma.
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References
Alhopuro P, Ylisaukko-Oja SK, Koskinen WJ, Bono P, Arola J, Järvinen HJ, Mecklin JP, Atula T, Kontio R, Mäkitie AA, Suominen S, Leivo I, Vahteristo P, Aaltonen LM, Aaltonen LA (2005) The MDM2 promoter polymorphism SNP309T–>G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck. J Med Genet 42:694–698
Almeida PS, Manoel WJ, Reis AA, Silva ER, Martins E, Paiva MV, Fraga AC Jr, Saddi VA (2008) TP53 codon 72 polymorphism in adult soft tissue sarcomas. Genet Mol Res 7:1344–1352
Arva NC, Gopen TR, Talbott KE, Campbell LE, Chicas A, White DE, Bond GL, Levine AJ, Bargonetti J (2005) A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. J Biol Chem 280:26776–26787
Barak Y, Juven T, Haffner R, Oren M (1993) mdm2 expression is induced by wild type p53 activity. EMBO J 12:461–468
Bergamaschi D, Samuels Y, Sullivan A, Zvelebil M, Breyssens H, Bisso A, Del Sal G, Syed N, Smith P, Gasco M, Crook T, Lu X (2006) iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat Genet 38:1133–1141
Bhagwat GP, Naik KG, Sachdeva R, Bhushan V (1980) Disseminated lymphadenopathic Kaposi’s sarcoma in Zambian children. Med J Zambia 14:61–63
Bond GL, Levine AJ (2007) A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 26:1317–1323
Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602
Bond GL, Hu W, Levine A (2005) A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res 65:5481–5484
Buonaguro FM, Tornesello ML, Beth-Giraldo E, Hatzakis A, Mueller N, Downing R, Biryamwaho B, Sempala SD, Giraldo G (1996) Herpesvirus-like DNA sequences detected in endemic, classic, iatrogenic and epidemic Kaposi’s sarcoma (KS) biopsies. Int J Cancer 65:25–28
Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865–1869
Chen J, Wu X, Lin J, Levine AJ (1996) mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. Mol Cell Biol 16:2445–2452
Cheok CF, Verma CS, Baselga J, Lane DP (2011) Translating p53 into the clinic. Nat Rev Clin Oncol 8:25–37
Clark MA, Fisher C, Judson I, Thomas JM (2005) Soft-tissue sarcomas in adults. N Engl J Med 353:701–711
Dumont P, Leu JI, Della Pietra AC 3rd, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33:357–365
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Eymin B, Gazzeri S, Brambilla C, Brambilla E (2002) Mdm2 overexpression and p14(ARF) inactivation are two mutually exclusive events in primary human lung tumors. Oncogene 21:2750–2761
Flørenes VA, Maelandsmo GM, Forus A, Andreassen A, Myklebost O, Fodstad O (1994) MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. J Natl Cancer Inst 86:1297–1302
Friborg J Jr, Kong W, Hottiger MO, Nabel GJ (1999) p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402:889–894
Gallo RC (1998) The enigmas of Kaposi’s sarcoma. Science 282:1837–1839
Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387:296–299
Hong Y, Miao X, Zhang X, Ding F, Luo A, Guo Y, Tan W, Liu Z, Lin D (2005) The role of P53 and MDM2 polymorphisms in the risk of esophageal squamous cell carcinoma. Cancer Res 65:9582–9587
HuGE Literature Finder (2011). http://hugenavigator.net/HuGENavigator/startPagePubLit.do
Ito M, Barys L, O’Reilly T, Young S, Gorbatcheva B, Monahan J, Zumstein-Mecker S, Choong PF, Dickinson I, Crowe P, Hemmings C, Desai J, Thomas DM, Lisztwan J (2011) Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin Cancer Res 17:416–426
Kotilingam D, Lev DC, Lazar AJ, Pollock RE (2006) Staging soft tissue sarcoma: evolution and change. CA Cancer J Clin 56:282–291 quiz 314–315
Landers JE, Cassel SL, George DL (1997) Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein. Cancer Res 57:3562–3568
Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, Hill DE, Sidransky D, Kinzler KW, Vogelstein B (1993) p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res 53:2231–2234
Lee HR, Toth Z, Shin YC, Lee JS, Chang H, Gu W, Oh TK, Kim MH, Jung JU (2009) Kaposi’s sarcoma-associated herpesvirus viral interferon regulatory factor 4 targets MDM2 to deregulate the p53 tumor suppressor pathway. J Virol 83:6739–6747
Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748
Meek DW (2009) Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer 9:714–723
Mirabello L, Troisi RJ, Savage SA (2009) Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 115:1531–1543
Oettle AG (1962) Geographical and racial differences in the frequency of Kaposi’s sarcoma as evidence of environmental or genetic causes. Acta Unio Int Contra Cancrum 18:330–363
Ørsted DD, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG (2007) Tumor suppressor p53 Arg72Pro polymorphism and longevity, cancer survival, and risk of cancer in the general population. J Exp Med 204:1295–1301
Ottaviani G, Jaffe N (2009) The epidemiology of osteosarcoma. Cancer Treat Res 152:3–13
Palmero EI, Achatz MI, Ashton-Prolla P, Olivier M, Hainaut P (2010) Tumor protein 53 mutations and inherited cancer: beyond Li-Fraumeni syndrome. Curr Opin Oncol 22:64–69
Petitti DB (1994) Of babies and bathwater. Am J Epidemiol 140:779–782
Polsky D, Bastian BC, Hazan C, Melzer K, Pack J, Houghton A, Busam K, Cordon-Cardo C, Osman I (2001) HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. Cancer Res 61:7642–7646
Rayburn E, Zhang R, He J, Wang H (2005) MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy. Curr Cancer Drug Targets 5:27–41
Savage SA, Burdett L, Troisi R, Douglass C, Hoover RN, Chanock SJ, National Osteosarcoma Etiology study group (2007) Germ-line genetic variation of TP53 in osteosarcoma. Pediatr Blood Cancer 49:28–33
Si H, Robertson ES (2006) Kaposi’s sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen induces chromosomal instability through inhibition of p53 function. J Virol 80:697–709
Siddique M, Sabapathy K (2006) Trp53-dependent DNA-repair is affected by the codon 72 polymorphism. Oncogene 25:3489–3500
Siegel JH, Janis R, Alper JC, Schutte H, Robbins L, Blaufox MD (1969) Disseminated visceral Kaposi’s sarcoma. Appearance after human renal homograft operation. JAMA 207:1493–1496
Slavin G, Cameron HM, Forbes C, Mitchell RM (1970) Kaposi’s sarcoma in East African children: a report of 51 cases. J Pathol 100:187–199
Toffoli G, Biason P, Russo A, De Mattia E, Cecchin E, Hattinger CM, Pasello M, Alberghini M, Ferrari C, Scotlandi K, Picci P, Serra M (2009) Effect of TP53 Arg72Pro and MDM2 SNP309 polymorphisms on the risk of high-grade osteosarcoma development and survival. Clin Cancer Res 15:3550–3556
Tornesello ML, Biryahwaho B, Downing R, Hatzakis A, Alessi E, Cusini M, Ruocco V, Katongole-Mbidde E, Buonaguro L, Buonaguro FM (2009) TP53 codon 72 polymorphism in classic, endemic and epidemic Kaposi’s sarcoma in African and Caucasian patients. Oncology 77:328–334
Tornesello ML, Buonaguro L, Cristillo M, Biryahwaho B, Downing R, Hatzakis A, Alessi E, Cusini M, Ruocco V, Viviano E, Romano N, Katongole-Mbidde E, Buonaguro FM (2011) MDM2 and CDKN1A gene polymorphisms and risk of Kaposi’s sarcoma in African and Caucasian patients. Biomarkers 16:42–50
US National Library of Medicine, National Institutes of Health (2011) PubMed home page. http://preview.ncbi.nlm.nih.gov/pubmed
Vesely K, Jurajda M, Nenutil R, Vesela M (2009) Expression of p53, cyclin D1 and EGFR correlates with histological grade of adult soft tissue sarcomas: a study on tissue microarrays. Neoplasma 56:239–244
Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310
Wunder JS, Eppert K, Burrow SR, Gokgoz N, Bell RS, Andrulis IL (1999) Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas. Oncogene 18:783–788
Yang M, Guo Y, Zhang X, Miao X, Tan W, Sun T, Zhao D, Yu D, Liu J, Lin D (2007) Interaction of P53 Arg72Pro and MDM2 T309G polymorphisms and their associations with risk of gastric cardia cancer. Carcinogenesis 28:1996–2001
Yu W, Gwinn M, Clyne M, Yesupriya A, Khoury MJ (2008) A navigator for human genome epidemiology. Nat Genet 40:124–125
Acknowledgments
This work was supported by Beijing Nova Program (no. 2010B013 to M. Yang) and the Fundamental Research Funds for the Central Universities (no. ZZ1234 to M. Yang).
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The authors declare no competing financial interests.
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Cai, X., Yang, M. The functional MDM2 T309G genetic variant but not P53 Arg72Pro polymorphism is associated with risk of sarcomas: a meta-analysis. J Cancer Res Clin Oncol 138, 555–561 (2012). https://doi.org/10.1007/s00432-011-1124-8
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DOI: https://doi.org/10.1007/s00432-011-1124-8