Research Papers:

Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649)

Stian Knappskog, Liv B. Gansmo, Khadizha Dibirova, Andres Metspalu, Cezary Cybulski, Paolo Peterlongo, Lauri Aaltonen, Lars Vatten, Pål Romundstad, Kristian Hveem, Peter Devilee, Gareth D. Evans, Dongxin Lin, Guy Van Camp, Vangelis G. Manolopoulos, Ana Osorio, Lili Milani, Tayfun Ozcelik, Pierre Zalloua, Francis Mouzaya, Elena Bliznetz, Elena Balanovska, Elvira Pocheshkova, Vaidutis Kučinskas, Lubov Atramentova, Pagbajabyn Nymadawa, Konstantin Titov, Maria Lavryashina, Yuldash Yusupov, Natalia Bogdanova, Sergey Koshel, Jorge Zamora, David C. Wedge, Deborah Charlesworth, Thilo Dörk, Oleg Balanovsky and Per E. Lønning _

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Oncotarget. 2014; 5:8223-8234. https://doi.org/10.18632/oncotarget.1910

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Stian Knappskog1,2, Liv B. Gansmo1,2, Khadizha Dibirova3, Andres Metspalu4, Cezary Cybulski5, Paolo Peterlongo6,7, Lauri Aaltonen8, Lars Vatten9 , Pål Romundstad9, Kristian Hveem9, Peter Devilee10,11, Gareth D. Evans12, Dongxin Lin13, Guy Van Camp14, Vangelis G. Manolopoulos15, Ana Osorio16, Lili Milani4, Tayfun Ozcelik17, Pierre Zalloua18, Francis Mouzaya18, Elena Bliznetz3, Elena Balanovska3, Elvira Pocheshkova19,Vaidutis Kučinskas20, Lubov Atramentova21, Pagbajabyn Nymadawa22, Konstantin Titov23, Maria Lavryashina24, Yuldash Yusupov25, Natalia Bogdanova26,27, Sergey Koshel28, Jorge Zamora29, David C. Wedge29, Deborah Charlesworth30, Thilo Dörk31, Oleg Balanovsky3,32 and Per E. Lønning1,2

1 Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway

2 Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway

3 Research Centre for Medical Genetics, Russian Academy of Medical Sciences, 115478 Moscow, Russia

4 Estonian Genome Center, University of Tartu, Tartu, Estonia

5 Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

6 IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy

7 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

8 Department of Medical Genetics, University of Helsinki, Helsinki 00014, Finland

9 Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway

10 Department of Human Genetics, Leiden University Medical Center, RC Leiden 2300, The Netherlands

11 Department of Pathology, Leiden University Medical Center, RC Leiden 2300, The Netherlands

12 Genetic Medicine, MAHSC, University of Manchester, St. Mary’s Hospital, Manchester, M13 OJH, UK

13 Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

14 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

15 Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece

16 Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, CNIO, Madrid, Spain

17 Bilkent University, Faculty of Science, Department of Molecular Biology and Genetics, Ankara, Turkey

18 Lebanese American University, Chouran, Beirut, Lebanon

19 Kuban Medical University, Krasnodar, Russia

20 Department of Human and Medical Genetics, Vilnius University, Faculty of Medicine, Vilnius, Lithuania

21 Department of Genetics and Cytology, Karazin Kharkiv National University, Kharkiv, Ukraine

22 Mongolian Academy of Medical Sciences, Ulaanbaatar, Mongolia

23 N.N. Blokhin Russian Cancer Research Center RAMS, Russia

24 Kemerovo State University, Kemerovo, Russia

25 Institute for Humanities Research of the Republic of Bashkortostan

26 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus

27 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany

28 Department of Cartography, Lomonosov Moscow State University, Moscow, Russia

29 Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK

30 University of Edinburgh, Institute of Evolutionary Biology, Edinburgh, Midlothian, Scotland

31 Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany

32 Vavilov Institute of General Genetics RAS, Moscow, Russia


Per Lønning, email:

Keywords: MDM2, SNP285, SNP309, polymorphism, promoter

Received: February 17, 2014 Accepted: April 16, 2014 Published: April 18, 2014



The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 – 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk.

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