title: SNP285C modulates oestrogen receptor/Sp1 binding to the MDM2 promoter and reduces the risk of endometrial but not prostatic cancer.
abstract: BACKGROUND
  The MDM2 promoter polymorphism (SNP309T > G) extends a binding site for the transcription factor Sp1 and has been linked to elevated cancer risk and/or young age at cancer diagnosis, especially in females. Recently, we reported an adjacent polymorphism (SNP285G > C). SNP285C antagonises the effect of SNP309G by reducing Sp1 binding and lowers the risk of breast and ovarian cancer.
  
  
  METHODS
  We assessed the potential gender specificity in the effect of this polymorphism. We performed in silico predictions of transcription factor binding sites in the MDM2 promoter and analysed MDM2 SNP285 and SNP309 status in two independent cohorts of endometrial (n = 438 and 472) and 666 prostatic cancer patients, and compared to 3.140 healthy controls.
  
  
  RESULTS
  We identified three oestrogen-receptor binding elements (EREs) within the MDM2 intronic promoter, one of which overlapping the Sp1 binding-site harbouring SNP285. The SNP285C/309G haplotype was associated with a reduced Odds Ratio (OR) for endometrial cancer (OR1: 0.55; Confidence Interval (CI) 0.32-0.97; OR2: 0.65; CI 0.40-1.08, especially for ER+ tumours; OR: 0.48; CI 0.28-0.87) but not for prostatic cancer among SNP309TG heterozygotes. SNP309G (SNP309TG or SNP309GG genotype) was associated with a moderately increased risk of endometrial cancer (OR: 1.17; CI 1.00-1.37) compared to SNP309TT homozygotes. Removing individuals harbouring the SNP309G-counteracting SNP285C polymorphism from the analysis strengthened this association (OR: 1.20; CI 1.02-1.41).
  
  
  CONCLUSIONS
  The finding of an ERE overlapping with the Sp1-binding site affected by SNP285, taken together with the significant impact of SNP285 on the risk of breast, ovarian and now endometrial cancer but not prostatic cancer, suggests a gender specific effect of SNP285C on cancer risk.
authors: Section of Oncology, Institute of Medicine, University of Bergen, Norway.
authors: Stian
authors: S
authors: Knappskog
authors: Jone
authors: J
authors: Trovik
authors: Janusz
authors: J
authors: Marcickiewicz
authors: Solveig
authors: S
authors: Tingulstad
authors: Annetine C
authors: AC
authors: Staff
authors: Pål
authors: P
authors: Romundstad
authors: Kristian
authors: K
authors: Hveem
authors: Lars
authors: L
authors: Vatten
authors: Helga B
authors: HB
authors: Salvesen
authors: Per E
authors: PE
authors: Lønning
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001665:Binding Sites / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism*; D012306:Risk; D012737:Sex Factors; D016329:Sp1 Transcription Factor / Q000378:metabolism*
chemical_list: D011960:Receptors, Estrogen; D016329:Sp1 Transcription Factor; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2