title: MDM2 SNP309 is associated with high grade node positive breast tumours and is in linkage disequilibrium with a novel MDM2 intron 1 polymorphism.
abstract: BACKGROUND
  A functional polymorphism within MDM2, SNP309 T>G, has been linked to early onset cancer. This study examined clinical associations of breast cancer with SNP309 in a Scottish Caucasian population and investigated additional MDM2 intron 1 polymorphisms.
  
  
  METHODS
  Intron 1 of MDM2 was PCR amplified and directly sequenced from 299 breast cancer patients and 275 cancer free controls and compared with clinical and pathological parameters.
  
  
  RESULTS
  SNP309 was observed, for the control and breast cancer cohorts respectively, at frequencies of: T/T = 44.7% and 39.5%; G/T = 42.2% and 47.2%; G/G = 13.1% and 13.4%, indicating that SNP309 is not a predisposing factor for breast cancer. The 309G/G genotype was associated with high grade tumours (OR = 1.64, 95%CI = 1.06-2.53, p = 0.025) and greater nodal involvement (OR = 2.51, 95%CI = 1.26-4.98, p = 0.009). SNP309 was not associated with an earlier age of cancer diagnosis. No association was observed between genotype and age of breast cancer diagnosis when patients were stratified by menopausal status and estrogen receptor status. Three additional low frequency SNPs were identified: 344T>A, 285G>C and 443G>T, the latter two novel. SNP285 was in complete linkage disequilibrium with SNP309 (D' = 1.0) with the minor alleles being in phase with each other. Moreover, the 285C/C, 309G/G double homozygous genotype was only observed in the breast cancer cohort.
  
  
  CONCLUSIONS
  SNP309G/G is associated with poor prognostic breast cancer features in the Scottish population. Additionally, a novel SNP, SNP285, that is in linkage disequilibrium with SNP309, may also have a role in breast tumorigenesis.
authors.affiliation: Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. f.e.m.paulin@dundee.ac.uk
authors.forename: Fiona E M
authors.initials: FE
authors.lastname: Paulin
authors.forename: Mary
authors.initials: M
authors.lastname: O'Neill
authors.forename: Gillian
authors.initials: G
authors.lastname: McGregor
authors.forename: Andrew
authors.initials: A
authors.lastname: Cassidy
authors.forename: Alison
authors.initials: A
authors.lastname: Ashfield
authors.forename: Clinton W
authors.initials: CW
authors.lastname: Ali
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Munro
authors.forename: Lee
authors.initials: L
authors.lastname: Baker
authors.forename: Colin A
authors.initials: CA
authors.lastname: Purdie
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D017668:Age of Onset; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D008593:Menopause; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D011960:Receptors, Estrogen / Q000032:analysis; D012044:Regression Analysis; D012606:Scotland
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2