title: A polymorphic variant in human MDM4 associates with accelerated age of onset of estrogen receptor negative breast cancer.
abstract: Murine double minute 4 (MDM4) shares significant structural homology with murine double minute 2 (MDM2) and interacts and regulates transcriptional activity of the tumor suppressor p53. In tumors with wild-type p53, there is often overexpression of MDM2 or MDM4 leading to functional inactivation of p53. A single-nucleotide polymorphism (SNP) in the promoter of human MDM2 (SNP309) was shown to associate with increased MDM2 expression and increased risk of cancer. This study evaluated the association of a SNP in human MDM4 (C>T) with age of onset of breast cancer in two independent cohorts. In cohort 1 of 675 patients, the average age of diagnosis for women with estrogen receptor (ER)-positive and ER-negative breast cancers was 53.2 and 48 years, respectively. In this cohort, homozygous variant (TT) carriers developed ER-negative carcinomas at an earlier age than homozygous wild-type (CC) or heterozygous (TC) such that the age at diagnosis was accelerated by 5.0 years (P = 0.018). This association was validated in a second cohort of breast cancer patients (n = 148), where TT carriers with ER-negative cancer developed the disease 3.8 years earlier than CC carriers (P = 0.006). The effect was more pronounced in Caucasians with ER-negative ductal carcinomas with TT homozygotes developing disease 7.5 years (P = 0.031) and 6.2 years (P = 7 x 10(-5)) earlier than CC carriers in cohorts 1 and 2, respectively. No association was seen in ER-positive ductal cancers suggesting that the SNP in MDM4 only has a functional association in ER-negative breast cancer.
authors.affiliation: Department of Medicine-Division of Medical Oncology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
authors.forename: Diptee A
authors.initials: DA
authors.lastname: Kulkarni
authors.forename: Alexei
authors.initials: A
authors.lastname: Vazquez
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Haffty
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.forename: Wenwei
authors.initials: W
authors.lastname: Hu
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Sun
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Toppmeyer
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hirshfield
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D044584:Carcinoma, Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53