Murine Double Minute Clone 2 309T/G and 285G/C Promoter Single Nucleotide Polymorphism as a Risk Factor for Breast Cancer: A Polish Experience

Background Breast cancer is a multifactorial disease caused by complex interactions between genetic and environmental factors. Recently, a functional polymorphism, MDM2 285G>C (rs117039649), has been discovered. This polymorphism antagonizes the effect of the 309T>G (rs2279744) polymorphism on the same gene, resulting in decreased MDM2 transcription. Methods The MDM2 285G>C and 309T>G polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing analysis in women with breast cancer (n=468) and controls (n=550). Results The odds ratio (OR) for breast cancer patients with the MDM2 285C/C and 285G/C genotypes was 0.4768 (95% confidence interval [CI] 0.2906–0.7824; p=0.0033, pcorr=0.0066). We also found a significantly lower frequency of the MDM2 285C allele in patients with breast cancer than in controls: the OR for the C allele in patients with breast cancer was 0.4930 (95% CI=0.3059–0.7947, p=0.0031, pcorr=0.0062). The p value of the chi-square test for the trend observed for the MDM2 285G>C polymorphism was statistically significant (ptrend=0.0036). The statistical power of this study amounted to 85% for the G/C or C/C genotypes and 85% for the C allele. However, we did not observe significant differences between the distribution of MDM2 309T>G genotypes and alleles in patients with breast cancer and healthy controls. Conclusion In a sample of the Polish population, we observed that the MDM2 285C gene variant may be a significant protective factor against breast cancer.

[1]  F Levi,et al.  European cancer mortality predictions for the year 2014. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

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

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

[4]  J. Ioannidis,et al.  Using lifetime risk estimates in personal genomic profiles: estimation of uncertainty. , 2009, American journal of human genetics.

[5]  T. Sergentanis,et al.  Differential effects of MDM2 SNP309 polymorphism on breast cancer risk along with race: a meta-analysis , 2010, Breast Cancer Research and Treatment.

[6]  J. Kaprio,et al.  Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. , 2000, The New England journal of medicine.

[7]  D. Ginsberg,et al.  p53 and E2f: partners in life and death , 2009, Nature Reviews Cancer.

[8]  C. la Vecchia,et al.  European cancer mortality predictions for the year 2011. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[9]  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.

[10]  R. Yarden,et al.  MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish–Ashkenazi descent , 2008, Breast Cancer Research and Treatment.

[11]  B. Vojtesek,et al.  MDM2SNP309 Does Not Associate with Elevated MDM2 Protein Expression or Breast Cancer Risk , 2008, Oncology.

[12]  Nazneen Rahman,et al.  The emerging landscape of breast cancer susceptibility , 2007, Nature Genetics.

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

[14]  T. Dörk,et al.  Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium. , 2007, Cancer research.

[15]  W. Sellers,et al.  Interaction between the retinoblastoma protein and the oncoprotein MDM2 , 1995, Nature.

[16]  Ling Yuan,et al.  MDM2 SNP309 polymorphism and breast cancer risk: a meta-analysis , 2011, Molecular Biology Reports.

[17]  J. Niland,et al.  The MDM2 gene amplification database. , 1998, Nucleic acids research.

[18]  A. Levine,et al.  Molecular Abnormalities of mdm 2 and p 53 Genes in Adult Soft Tissue Sarcomas ' , 2022 .

[19]  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.

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

[21]  Hongbing Shen,et al.  MDM2 Promoter Polymorphism SNP309 Contributes to Tumor Susceptibility: Evidence from 21 Case-Control Studies , 2007, Cancer Epidemiology Biomarkers & Prevention.

[22]  N. Dalay,et al.  ARLTS1, MDM2 and RAD51 gene variations are associated with familial breast cancer , 2010, Molecular Biology Reports.

[23]  A. Levine,et al.  Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. , 1994, Cancer research.

[24]  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.

[25]  Paola Pisani,et al.  Estimates of the world‐wide prevalence of cancer for 25 sites in the adult population , 2002, International journal of cancer.

[26]  Tony Kouzarides,et al.  Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein , 1995, Nature.

[27]  J. Benítez,et al.  The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers , 2009, British Journal of Cancer.

[28]  A. Levine,et al.  A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans , 2007, Oncogene.

[29]  P. Meltzer,et al.  Advances in Brief p 53 Mutation and MDM 2 Amplification in Human Soft Tissue Sarcomas 1 , 2006 .

[30]  C. M. Eischen,et al.  Mdm2 Binds to Nbs1 at Sites of DNA Damage and Regulates Double Strand Break Repair* , 2005, Journal of Biological Chemistry.

[31]  M J Gaffey,et al.  Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. , 1995, American journal of clinical pathology.

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

[33]  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.

[34]  J. Landers,et al.  Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein. , 1997, Cancer research.

[35]  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.

[36]  Lester L. Peters,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2007, Nature.

[37]  Hongbing Shen,et al.  MDM 2 Promoter Polymorphism SNP 309 Contributes to Tumor Susceptibility : Evidence from 21 Case-Control Studies , 2007 .

[38]  Dongxin Lin,et al.  The MDM2 promoter SNP285C/309G haplotype diminishes Sp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians. , 2011, Cancer cell.

[39]  K. Hemminki,et al.  MDM2 SNP309 and cancer risk: a combined analysis. , 2007, Carcinogenesis.

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

[41]  U. Francke,et al.  Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line , 1987, Somatic cell and molecular genetics.

[42]  N. Mathur,et al.  Association of polymorphism in MDM-2 and p53 genes with breast cancer risk in Indian women. , 2008, Annals of epidemiology.

[43]  Wei Zheng,et al.  Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. , 2011, The Lancet. Oncology.

[44]  A. Levine,et al.  The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation , 1992, Cell.

[45]  D. George,et al.  Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. , 1991, The EMBO journal.

[46]  Z. Shao,et al.  MDM2 SNP309 G allele increases risk but the T allele is associated with earlier onset age of sporadic breast cancers in the Chinese population. , 2008, Carcinogenesis.

[47]  A. Thompson,et al.  MDM2 SNP309 is associated with high grade node positive breast tumours and is in linkage disequilibrium with a novel MDM2 intron 1 polymorphism , 2008, BMC Cancer.

[48]  G. Zambetti,et al.  Mdm‐2: “big brother” of p53 , 1997, Journal of cellular biochemistry.

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

[50]  H. Taubert,et al.  Amplification of the mdm2 gene, but not expression of splice variants of mdm2 mrna, is associated with prognosis in soft tissue sarcoma , 2001, International journal of cancer.

[51]  Yi-Jang Lee,et al.  Results based on 124 cases of breast cancer and 97 controls from Taiwan suggest that the single nucleotide polymorphism (SNP309) in the MDM2 gene promoter is associated with earlier onset and increased risk of breast cancer , 2009, BMC Cancer.