The MDM2 Promoter SNP285C/309G Haplotype Diminishes Sp1 Transcription Factor Binding and Reduces Risk for Breast and Ovarian Cancer in Caucasians
- Knappskog, Stian
- Bjørnslett, Merete
- Myklebust, Line M.
- Huijts, Petra E.A.
- Vreeswijk, Maaike P.
- Edvardsen, Hege
- Guo, Yongli
- Zhang, Xuemei
- Yang, Ming
- Ylisaukko-oja, Sanna K.
- Alhopuro, Pia
- Arola, Johanna
- Tollenaar, Rob A.E.M.
- van Asperen, Christi J.
- Seynaeve, Caroline
- Staalesen, Vidar
- Chrisanthar, Ranjan
- Løkkevik, Erik
- Salvesen, Helga B.
- Evans, D. Gareth
- Newman, William G.
- Lin, Dongxin
- Aaltonen, Lauri A.
- Børresen-Dale, Anne-Lise
- Tell, Grethe S.
- Stoltenberg, Camilla
- Romundstad, Pål
- Hveem, Kristian
- Lillehaug, Johan R.
- Vatten, Lars
- Devilee, Peter
- Dørum, Anne
- Lønning, Per E.
DOIAbstract
SummaryMDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%–7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58–0.94) an...
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