DOI: 10.1158/1078-0432.ccr-07-0609. <i>MDM2</i> SNP309 Polymorphism as Risk Factor for Susceptibility and Poor Prognosis in Renal Cell Carcinoma

MDM2 SNP309 Polymorphism as Risk Factor for Susceptibility and Poor Prognosis in Renal Cell Carcinoma

10.1158/1078-0432.ccr-07-0609

Crossref journal-article

American Association for Cancer Research (AACR)

Clinical Cancer Research (1086)

Abstract

Abstract Purpose: MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism in the MDM2 promoter region SNP309 (rs2279744) has been shown to increase the affinity of the transcriptional activator Sp1, resulting in elevated MDM2 transcription and expression in some cancers. There is currently no information about the role of MDM2 polymorphism in renal cell carcinoma (RCC). We investigated polymorphisms in p53-related genes, including MDM2, and their interactions in renal cancer. Experimental Design: We genotyped three single nucleotide polymorphisms of three genes (p53 Arg72Pro, p21 Ser31Arg, and MDM2 SNP309) in 200 patients with renal cancer and 200 age- and gender-matched healthy subjects. Genotyping was confirmed by direct DNA sequencing. Samples that showed significant polymorphic variants were analyzed for MDM2 expression by immunohistochemistry. Association of polymorphic variants on survival of RCC patients was analyzed by Kaplan-Meier curves. Results: A significant increase in the GG genotype of the MDM2 SNP309 was observed in RCC patients compared with healthy controls (odds ratio, 1.80; 95% confidence interval, 1.14-2.84). To investigate the effect of the MDM2 SNP309 polymorphism on MDM2 expression, immunohistochemistry was done in genotyped RCC tissues. Positive staining for MDM2 was detected in 2 of 15 (13%) TT genotype, 4 of 15 (26%) TG genotype, and 5 of 10 (50%) GG genotype carriers. The frequency of MDM2 expression in GG genotype carriers was significantly higher than that in TT genotype carriers. Polymorphisms of p53 Arg72Pro and p21 Ser31Arg did not show significant association with RCC. In univariate and multivariate analysis, MDM2 SNP309 GG genotype was independently associated with poor prognosis. Kaplan-Meier curve analysis showed that survival of patients with GG carriers was significantly worse than that of carriers with TG + TT genotypes. Conclusions: This is the first report to show a significant association between functional polymorphisms in MDM2 and increased risk of developing renal cancer. In addition, the MDM2 polymorphism was shown to be an independent adverse prognostic factor for RCC. Patients with MDM2 309GG genotype showed worse prognosis and low survival.

Bibliography

Hirata, H., Hinoda, Y., Kikuno, N., Kawamoto, K., Suehiro, Y., Tanaka, Y., & Dahiya, R. (2007). MDM2 SNP309 Polymorphism as Risk Factor for Susceptibility and Poor Prognosis in Renal Cell Carcinoma. Clinical Cancer Research, 13(14), 4123â4129.

Authors 7

Hiroshi Hirata (first)
Yuji Hinoda (additional)
Nobuyuki Kikuno (additional)
Ken Kawamoto (additional)
Yutaka Suehiro (additional)
Yuichiro Tanaka (additional)
Rajvir Dahiya (additional)

References 34 Referenced 72

Dates

Type	When
Created	18 years, 1 month ago (July 18, 2007, 8:27 p.m.)
Deposited	3 years, 2 months ago (June 11, 2022, 4:34 p.m.)
Indexed	1 year ago (Aug. 30, 2024, 9:52 a.m.)
Issued	18 years, 1 month ago (July 15, 2007)
Published	18 years, 1 month ago (July 15, 2007)
Published Online	18 years, 1 month ago (July 18, 2007)
Published Print	18 years, 1 month ago (July 15, 2007)

Funders 0

None

BibTeX

@article{Hirata_2007, title={MDM2 SNP309 Polymorphism as Risk Factor for Susceptibility and Poor Prognosis in Renal Cell Carcinoma}, volume={13}, ISSN={1557-3265}, url={http://dx.doi.org/10.1158/1078-0432.ccr-07-0609}, DOI={10.1158/1078-0432.ccr-07-0609}, number={14}, journal={Clinical Cancer Research}, publisher={American Association for Cancer Research (AACR)}, author={Hirata, Hiroshi and Hinoda, Yuji and Kikuno, Nobuyuki and Kawamoto, Ken and Suehiro, Yutaka and Tanaka, Yuichiro and Dahiya, Rajvir}, year={2007}, month=jul, pages={4123–4129} }

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  "abstract": "<jats:title>Abstract</jats:title>\n               <jats:p>Purpose: MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism in the MDM2 promoter region SNP309 (rs2279744) has been shown to increase the affinity of the transcriptional activator Sp1, resulting in elevated MDM2 transcription and expression in some cancers. There is currently no information about the role of MDM2 polymorphism in renal cell carcinoma (RCC). We investigated polymorphisms in p53-related genes, including MDM2, and their interactions in renal cancer.</jats:p>\n               <jats:p>Experimental Design: We genotyped three single nucleotide polymorphisms of three genes (p53 Arg72Pro, p21 Ser31Arg, and MDM2 SNP309) in 200 patients with renal cancer and 200 age- and gender-matched healthy subjects. Genotyping was confirmed by direct DNA sequencing. Samples that showed significant polymorphic variants were analyzed for MDM2 expression by immunohistochemistry. Association of polymorphic variants on survival of RCC patients was analyzed by Kaplan-Meier curves.</jats:p>\n               <jats:p>Results: A significant increase in the GG genotype of the MDM2 SNP309 was observed in RCC patients compared with healthy controls (odds ratio, 1.80; 95% confidence interval, 1.14-2.84). To investigate the effect of the MDM2 SNP309 polymorphism on MDM2 expression, immunohistochemistry was done in genotyped RCC tissues. Positive staining for MDM2 was detected in 2 of 15 (13%) TT genotype, 4 of 15 (26%) TG genotype, and 5 of 10 (50%) GG genotype carriers. The frequency of MDM2 expression in GG genotype carriers was significantly higher than that in TT genotype carriers. Polymorphisms of p53 Arg72Pro and p21 Ser31Arg did not show significant association with RCC. In univariate and multivariate analysis, MDM2 SNP309 GG genotype was independently associated with poor prognosis. Kaplan-Meier curve analysis showed that survival of patients with GG carriers was significantly worse than that of carriers with TG + TT genotypes.</jats:p>\n               <jats:p>Conclusions: This is the first report to show a significant association between functional polymorphisms in MDM2 and increased risk of developing renal cancer. In addition, the MDM2 polymorphism was shown to be an independent adverse prognostic factor for RCC. Patients with MDM2 309GG genotype showed worse prognosis and low survival.</jats:p>",
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      "unstructured": "Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin\u20082000;50:7\u201333.",
      "DOI": "10.3322/canjclin.50.1.7"
    },
    {
      "key": "2022061105335055900_B2",
      "doi-asserted-by": "crossref",
      "unstructured": "Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol\u20082004;22:4991\u20135004.",
      "DOI": "10.1200/JCO.2004.05.061"
    },
    {
      "key": "2022061105335055900_B3",
      "doi-asserted-by": "crossref",
      "unstructured": "Gnarra JR, Tory K, Weng Y, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet\u20081994;7:85\u201390.",
      "DOI": "10.1038/ng0594-85"
    },
    {
      "key": "2022061105335055900_B4",
      "doi-asserted-by": "crossref",
      "unstructured": "Pischon T, Lahmann PH, Boeing H, et al. Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer\u20082006;118:728\u201338.",
      "DOI": "10.1002/ijc.21398"
    },
    {
      "key": "2022061105335055900_B5",
      "doi-asserted-by": "crossref",
      "unstructured": "Semenza JC, Ziogas A, Largent J, Peel D, Anton-Culver H. Gene-environment interactions in renal cell carcinoma. Am J Epidemiol\u20082001;153:851\u20139.",
      "DOI": "10.1093/aje/153.9.851"
    },
    {
      "key": "2022061105335055900_B6",
      "doi-asserted-by": "crossref",
      "unstructured": "Levine AJ. p53, the cellular gatekeeper for growth and division. Cell\u20081997;88:323\u201331.",
      "DOI": "10.1016/S0092-8674(00)81871-1"
    },
    {
      "key": "2022061105335055900_B7",
      "doi-asserted-by": "crossref",
      "unstructured": "Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature\u20081993;366:701\u20134.",
      "DOI": "10.1038/366701a0"
    },
    {
      "key": "2022061105335055900_B8",
      "doi-asserted-by": "crossref",
      "unstructured": "Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature\u20081997;387:296\u20139.",
      "DOI": "10.1038/387296a0"
    },
    {
      "key": "2022061105335055900_B9",
      "doi-asserted-by": "crossref",
      "unstructured": "Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature\u20081997;387:299\u2013303.",
      "DOI": "10.1038/387299a0"
    },
    {
      "key": "2022061105335055900_B10",
      "doi-asserted-by": "crossref",
      "unstructured": "Bond GL, Hu W, Levine A. A single nucleotide polymorphism in the MDM2 gene from a molecular and cellular explanation to clinical effect. Cancer Res\u20082005;65:5481\u20134.",
      "DOI": "10.1158/0008-5472.CAN-05-0825"
    },
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      "key": "2022061105335055900_B11",
      "doi-asserted-by": "crossref",
      "unstructured": "Boersma BJ, Howe TM, Goodman JE, et al. Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst\u20082006;98:911\u20139.",
      "DOI": "10.1093/jnci/djj245"
    },
    {
      "key": "2022061105335055900_B12",
      "doi-asserted-by": "crossref",
      "unstructured": "Santos AM, Sousa H, Pinto D, et al. Linking TP53 codon 72 and P21 nt590 genotypes to the development of cervical and ovarian cancer. Eur J Cancer\u20082006;42:958\u201363.",
      "DOI": "10.1016/j.ejca.2006.01.015"
    },
    {
      "key": "2022061105335055900_B13",
      "doi-asserted-by": "crossref",
      "unstructured": "Schabath MB, Wu X, Wei Q, Li G, Gu J, Spitz MR. Combined effects of the p53 and p73 polymorphisms on lung cancer risk. Cancer Epidemiol Biomarkers Prev\u20082006;15:158\u201361.",
      "DOI": "10.1158/1055-9965.EPI-05-0622"
    },
    {
      "key": "2022061105335055900_B14",
      "doi-asserted-by": "crossref",
      "unstructured": "Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol\u20081999;19:1092\u2013100.",
      "DOI": "10.1128/MCB.19.2.1092"
    },
    {
      "key": "2022061105335055900_B15",
      "unstructured": "Kibel AS, Suarez BK, Belani J, et al. CDKN1A and CDKN1B polymorphisms and risk of advanced prostate carcinoma. Cancer Res\u20082003;63:2033\u20136."
    },
    {
      "key": "2022061105335055900_B16",
      "doi-asserted-by": "crossref",
      "unstructured": "Li G, Liu Z, Sturgis EM, et al. Genetic polymorphisms of p21 are associated with risk of squamous cell carcinoma of the head and neck. Carcinogenesis\u20082005;26:1596\u2013602.",
      "DOI": "10.1093/carcin/bgi105"
    },
    {
      "key": "2022061105335055900_B17",
      "doi-asserted-by": "crossref",
      "unstructured": "Su L, Sai Y, Fan R, et al. P53 (codon 72) and P21 (codon 31) polymorphisms alter in vivo mRNA expression of p21. Lung Cancer\u20082003;40:259\u201366.",
      "DOI": "10.1016/S0169-5002(03)00081-3"
    },
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      "key": "2022061105335055900_B18",
      "doi-asserted-by": "crossref",
      "unstructured": "Bond GL, Hu W, Bond EE, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell\u20082004;119:591\u2013602.",
      "DOI": "10.1016/j.cell.2004.11.022"
    },
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      "key": "2022061105335055900_B19",
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      "unstructured": "Lind H, Zienolddiny S, Ekstrom PO, Skauq V, Haugen A. Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer. Int J Cancer\u20082006;119:718\u201321.",
      "DOI": "10.1002/ijc.21872"
    },
    {
      "key": "2022061105335055900_B20",
      "doi-asserted-by": "crossref",
      "unstructured": "Hong Y, Miao X, Zhang X, et al. The role of P53 and MDM2 polymorphisms in the risk of esophageal squamous cell carcinoma. Cancer Res\u20082005;65:9582\u20137.",
      "DOI": "10.1158/0008-5472.CAN-05-1460"
    },
    {
      "key": "2022061105335055900_B21",
      "doi-asserted-by": "crossref",
      "unstructured": "Ohmiya N, Taguchi A, Mabuchi N, et al. MDM2 promoter polymorphism is associated with both an increased susceptibility to gastric carcinoma and poor prognosis. J Clin Oncol\u20082006;20:4434\u201340.",
      "DOI": "10.1200/JCO.2005.04.1459"
    },
    {
      "key": "2022061105335055900_B22",
      "unstructured": "Haitel A, Wiener HG, Baethge U, Marberger M, Susani M. mdm2 expression as a prognostic indicator in clear cell renal cell carcinoma: comparison with p53 overexpression and clinicopathological parameters. Clin Cancer Res\u20082000;6:1840\u20134."
    },
    {
      "key": "2022061105335055900_B23",
      "doi-asserted-by": "crossref",
      "unstructured": "Uchida T, Gao JP, Wang C, et al. Clinical significance of p53, mdm2, and bcl-2 proteins in renal cell carcinoma. Urology\u20082002;59:615\u201320.",
      "DOI": "10.1016/S0090-4295(01)01601-6"
    },
    {
      "key": "2022061105335055900_B24",
      "doi-asserted-by": "crossref",
      "unstructured": "Weiss RH, Borowsky AD, Seligson D, et al. p21 is a prognostic marker for renal cell carcinoma: implications for novel therapeutic approaches. J Urol\u20082007;177:63\u20138.",
      "DOI": "10.1016/j.juro.2006.08.073"
    },
    {
      "key": "2022061105335055900_B25",
      "doi-asserted-by": "crossref",
      "unstructured": "Menin C, Scaini MC, De Salvo GL, et al. Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. J Natl Cancer Inst\u20082006;98:285\u20138.",
      "DOI": "10.1093/jnci/djj054"
    },
    {
      "key": "2022061105335055900_B26",
      "unstructured": "Keshava C, Frye BL, Wolff MS, McCanlies EC, Weston A. Waf-1 (p21) and p53 polymorphisms in breast cancer. Cancer Epidemiol Biomarkers Prev\u20082002;11:127\u201330."
    },
    {
      "key": "2022061105335055900_B27",
      "doi-asserted-by": "crossref",
      "unstructured": "Xi YG, Ding KY, Su XL, et al. p53 polymorphism and p21WAF1/CIP1 haplotype in the intestinal gastric cancer and the precancerous lesions. Carcinogenesis\u20082004;25:2201\u20136.",
      "DOI": "10.1093/carcin/bgh229"
    },
    {
      "key": "2022061105335055900_B28",
      "doi-asserted-by": "crossref",
      "unstructured": "Ara S, Lee PS, Hansen MF, Saya H. Codon 72 polymorphism of the TP53 gene. Nucleic Acids Res\u20081990;18:4961.",
      "DOI": "10.1093/nar/18.16.4961"
    },
    {
      "key": "2022061105335055900_B29",
      "doi-asserted-by": "crossref",
      "unstructured": "Sotamaa K, Liyanarachchi S, Mecklin JP, et al. p53 codon 72 and MDM2 SNP309 polymorphisms and age of colorectal cancer onset in Lynch syndrome. Clin Cancer Res\u20082005;11:6840\u20134.",
      "DOI": "10.1158/1078-0432.CCR-05-1139"
    },
    {
      "key": "2022061105335055900_B30",
      "doi-asserted-by": "crossref",
      "unstructured": "Onel K, Cordon-Cardo C. MDM2 and prognosis. Mol Cancer Res\u20082004;2:1\u20138.",
      "DOI": "10.1158/1541-7786.1.2.1"
    },
    {
      "key": "2022061105335055900_B31",
      "doi-asserted-by": "crossref",
      "unstructured": "Parker SB, Eichele G, Zhang P, et al. p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science\u20081995;267:1024\u20137.",
      "DOI": "10.1126/science.7863329"
    },
    {
      "key": "2022061105335055900_B32",
      "doi-asserted-by": "crossref",
      "unstructured": "Papandreou CN, Bogenrieder T, Loganzo F, Albino AP, Nanus D. Expression and sequence analysis of the p21 (WAF1/CIP1) gene in renal cancers. Urology\u20081997;49:481\u20136.",
      "DOI": "10.1016/S0090-4295(96)00493-1"
    },
    {
      "key": "2022061105335055900_B33",
      "doi-asserted-by": "crossref",
      "unstructured": "Freedman DA, Levine AJ. Regulation of the p53 protein by the MDM2 oncoprotein\u2014thirty-eighth G.H.A. Clowes Memorial Award Lecture. Cancer Res\u20081999;59:1\u20137.",
      "DOI": "10.1007/s000180050273"
    },
    {
      "key": "2022061105335055900_B34",
      "doi-asserted-by": "crossref",
      "unstructured": "Malkin D, Li FP, Strong LC. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science\u20081990;250:1233\u20138.",
      "DOI": "10.1126/science.1978757"
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