Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649)
Knappskog, Stian; Gansmo, Liv Beathe; Dibirova, Khadizha; Metspalu, Andres; Cybulski, Cezary; Peterlongo, Paolo; Aaltonen, Lauri; Vatten, Lars Johan; Romundstad, Pål Richard; Hveem, Kristian; Devilee, Peter; Evans, Gareth D; Lin, Dongxin; Van Camp, Guy; Manolopoulos, Vangelis G; Osorio, Ana; Milani, Lili; Ozcelik, Tayfun; Zalloua, Pierre; Mouzaya, Francis; Bliznetz, Elena; Balanovska, Elena; Pocheshkova, Elvira; Kucinskas, Vaidutis; Atramentova, Lubov; Nymadawa, Pagbajabyn; Titov, Konstantin; Lavryashina, Maria; Yusupov, Yuldash; Bogdanova, Natalia; Koshel, Sergey; Zamora, Jorge; Wedge, David C.; Charlesworth, Deborah; Dörk, Thilo; Balanovsky, Oleg; Lønning, Per Eystein
Original version
Oncotarget 2014, 5(18):8223-8234Abstract
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.