MDM2 Promoter Polymorphism SNP309 Contributes to Tumor Susceptibility: Evidence from 21 Case-Control Studies

Since the identification of a well-characterized functional polymorphism named SNP309 in MDM2, abundant studies were published in the last 2 years to evaluate the association between SNP309 and tumor risk in diverse populations. However, the results remain conflicting rather than conclusive. Because a single study may have been underpowered to detect the effect of low-penetrance genes, a quantitative synthesis to accumulate data from different studies may provide better evidence on the association of genetic variant with tumor susceptibility. We conducted a meta-analysis on 14,770 cases with different tumor types and 14,524 controls from 25 published case-control studies to estimate the effect of SNP309 on tumor risk, as well as to quantify the potential between-study heterogeneity. We found that variant homozygote 309GG was associated with a significantly increased risk of all types of tumors [homozygote comparison: odds ratio (OR), 1.17, 95% confidential interval (95% CI), 1.04-1.33, P = 0.0002 for heterogeneity test; recessive model comparison: OR, 1.15, 95% CI, 1.03-1.28, P = 0.0005 for heterogeneity test]. Tumor type and ethnicity contributed to the substantial heterogeneity (69.5% for homozygote comparison and 77.2% for recessive model comparison). The analyses suggest that MDM2 SNP309 serves as a low-penetrance susceptibility tumor marker. Further large studies incorporate quantitative detection of different p53-responsible environmental stresses, p53 mutation status, and also functional genetic variants in p53-MDM2–related genes are warranted. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2717–23)

[1]  K. Hemminki,et al.  No association between MDM2 SNP309 promoter polymorphism and basal cell carcinoma of the skin , 2007, The British journal of dermatology.

[2]  R. Dahiya,et al.  MDM2 SNP309 Polymorphism as Risk Factor for Susceptibility and Poor Prognosis in Renal Cell Carcinoma , 2007, Clinical Cancer Research.

[3]  F. He,et al.  MDM2 Promoter SNP309 Is Associated with Risk of Occurrence and Advanced Lymph Node Metastasis of Nasopharyngeal Carcinoma in Chinese Population , 2007, Clinical Cancer Research.

[4]  Gustavo Stolovitzky,et al.  A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells. , 2007, Cancer research.

[5]  Carl W. Miller,et al.  Association between a functional single nucleotide polymorphism in the MDM2 gene and sporadic endometrial cancer risk. , 2007, Gynecologic oncology.

[6]  D. Malkin,et al.  Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. , 2007, Cancer research.

[7]  David J. Hunter,et al.  The p53 Arg72Pro and MDM2 -309 polymorphisms and risk of breast cancer in the nurses’ health studies , 2006, Cancer Causes & Control.

[8]  Hiroyuki Yamamoto,et al.  Tumour selection advantage of non-dominant negative P53 mutations in homozygotic MDM2-SNP309 colorectal cancer cells , 2006, Journal of Medical Genetics.

[9]  L. J. Veer,et al.  The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li–Fraumeni syndrome and related phenotypes , 2007, European Journal of Human Genetics.

[10]  J. Klijn,et al.  MDM2 SNP309 accelerates familial breast carcinogenesis independently of estrogen signaling , 2007, Breast Cancer Research and Treatment.

[11]  I. Yulug,et al.  Lack of association between the MDM2-SNP309 polymorphism and breast cancer risk. , 2006, Anticancer research.

[12]  J. Park,et al.  MDM2 309T>G polymorphism and risk of lung cancer in a Korean population. , 2006, Lung cancer.

[13]  M. Spitz,et al.  MDM2 gene promoter polymorphisms and risk of lung cancer: a case-control analysis. , 2006, Carcinogenesis.

[14]  Y. Hirooka,et al.  MDM2 promoter polymorphism is associated with both an increased susceptibility to gastric carcinoma and poor prognosis. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  T. Ozcelik,et al.  MDM2 T309G polymorphism is associated with bladder cancer. , 2006, Anticancer research.

[16]  D. Eccles,et al.  No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer. , 2006, Cancer letters.

[17]  Hongbing Shen,et al.  Polymorphisms in the MDM2 promoter and risk of breast cancer: a case-control analysis in a Chinese population. , 2006, Cancer letters.

[18]  N. Kato,et al.  MDM2 Promoter SNP309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C , 2006, Clinical Cancer Research.

[19]  E. Bowman,et al.  MDM2 SNP309 and SNP354 Are Not Associated with Lung Cancer Risk , 2006, Cancer Epidemiology Biomarkers & Prevention.

[20]  S. Zienolddiny,et al.  Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer , 2006, International journal of cancer.

[21]  Julie E Goodman,et al.  Association of breast cancer outcome with status of p53 and MDM2 SNP309. , 2006, Journal of the National Cancer Institute.

[22]  A. Levine,et al.  MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. , 2006, Cancer research.

[23]  Hongbing Shen,et al.  Genetic variants in the MDM2 promoter and lung cancer risk in a Chinese population , 2006, International journal of cancer.

[24]  R. Bertorelle,et al.  Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. , 2006, Journal of the National Cancer Institute.

[25]  P. Bugert,et al.  The single nucleotide polymorphism IVS1+309 in mouse double minute 2 does not affect risk of familial breast cancer. , 2006, Cancer research.

[26]  C. Prives,et al.  Unleashing the power of p53: lessons from mice and men. , 2006, Genes & development.

[27]  Wen Tan,et al.  Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer , 2006, Human mutation.

[28]  R. Millikan,et al.  No Association Between the MDM2 −309 T/G Promoter Polymorphism and Breast Cancer in African-Americans or Whites , 2006, Cancer Epidemiology Biomarkers & Prevention.

[29]  N. Kato,et al.  MDM 2 Promoter SNP 309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C , 2006 .

[30]  D. Eccles,et al.  Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers , 2006, BMC Cancer.

[31]  C. Bonaïti‐pellié,et al.  Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome , 2005, Journal of Medical Genetics.

[32]  W. Tan,et al.  The role of P53 and MDM2 polymorphisms in the risk of esophageal squamous cell carcinoma. , 2005, Cancer research.

[33]  L. Aaltonen,et al.  The MDM2 promoter polymorphism SNP309T→G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck , 2005, Journal of Medical Genetics.

[34]  A. Levine,et al.  A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. , 2005, Cancer research.

[35]  A. Levine,et al.  The p53 pathway: positive and negative feedback loops , 2005, Oncogene.

[36]  Ruiwen Zhang,et al.  p53-independent activities of MDM2 and their relevance to cancer therapy. , 2005, Current cancer drug targets.

[37]  N. Sneige,et al.  Abnormal expression of MDM-2 in breast carcinomas , 2005, Breast Cancer Research and Treatment.

[38]  A. Levine,et al.  A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans , 2004, Cell.

[39]  Cancer Epidemiol Biomarkers Prev , 2004 .

[40]  C. Harris,et al.  TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. , 2004, IARC scientific publications.

[41]  J. Blaydes,et al.  p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. , 2003, Cancer research.

[42]  S. Nakashima,et al.  Distinct promoter usage of mdm2 gene in human breast cancer. , 2002, Oncology reports.

[43]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[44]  H. Horvitz,et al.  Genetic control of programmed cell death in the nematode Caenorhabditis elegans. , 1999, Cancer research.

[45]  J. Ioannidis,et al.  Quantitative Synthesis in Systematic Reviews , 1997, Annals of Internal Medicine.

[46]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.

[47]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[48]  M. Oren,et al.  A functional p53-responsive intronic promoter is contained within the human mdm2 gene. , 1995, Nucleic acids research.

[49]  A. Marchetti,et al.  mdm2 gene alterations and mdm2 protein expression in breast carcinomas , 1995, The Journal of pathology.

[50]  R. Koff,et al.  Meta-analysis, decision analysis, and cost-effectiveness analysis. Methods for quantitative synthesis in medicine , 1995 .

[51]  H. Nguyen,et al.  Differential expression of multiple MDM2 messenger RNAs and proteins in normal and tumorigenic breast epithelial cells. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[52]  M. Oren,et al.  Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. , 1994, Genes & development.

[53]  P. Meltzer,et al.  p53 Mutation and MDM2 amplification in human soft tissue sarcomas. , 1993, Cancer research.

[54]  P. Meltzer,et al.  Amplification of a gene encoding a p53-associated protein in human sarcomas , 1992, Nature.

[55]  A Whitehead,et al.  A general parametric approach to the meta-analysis of randomized clinical trials. , 1991, Statistics in medicine.