Carcinogenesis Advance Access originally published online on September 16, 2009
Carcinogenesis 2009 30(11):1910-1915; doi:10.1093/carcin/bgp224
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A polymorphic variant in human MDM4 associates with accelerated age of onset of estrogen receptor negative breast cancer
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
1 The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540, USA
2 Department of Radiation Oncology
3 Department of Surgical Oncology
4 Department of Pediatrics, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jerse-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
* To whom correspondence should be addressed. Tel: +1 732 235 6028; Fax: +1 732 235 5331; Email: hirshfie{at}umdnj.edu
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.
Abbreviations: ER, estrogen receptor; MDM2, murine double minute 2; MDM4, murine double minute 4; SNP, single-nucleotide polymorphism
Received June 18, 2009; revised August 19, 2009; accepted September 5, 2009.