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

Abstract

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.

Evaluation of TP53 Pro72Arg and MDM2 SNP285–SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations

“…The SNP285C variant resides on the SNP309G allele and creates a distinct SNP285C/309G haplotype, typical of the Caucasian population [32]. In vitro analyses indicated that this SNP neutralizes the 309G variation effect, with reduced risk in different cancer types [33]; we did not detect this effect in our population.…”

“…285G[C, Chr12(GRCh37): g.69202556G[C: rs117039649)-has recently been described within the MDM2 promoter [12]. Population studies revealed that the SNP285C variant has occurred on the SNP309G allele and is present only in Caucasians, so defining only three possible haplotypes: 285G-309T, 285G-309G, 285C-309G [30,32]. In vitro analyses showed that the 285C variation is able to antagonize the effect of the 309G variation through a reduction of the Sp1 transcription factor binding strength to the MDM2 promoter [30]; this effect was confirmed by Renaux-Petel et al [12] who associated the MDM2 285G-309G haplotype with an earlier age of tumour onset in patients with Li-Fraumeni syndrome.…”

Homozygous G/G variant of SNP309 in the human MDM2 gene is associated with earlier tumor onset in Caucasian female renal cell carcinoma patients

“…17 Interestingly, the SNP285C allele is absent in Asian populations (Han Chinese and Mongolians) and African Americans but is a pan-Caucasian variant that occurs in approximately 6–8% of the Caucasian population and at lower frequencies in Finns and Sami populations. 18 Knappskog and Lønning suggested that the studies performed on the SNP285C-free Asian cohorts represent the ‘true' effect of SNP309G, whereas the studies in Western Europe need to be ‘corrected' with respect to SNP285 status. 17 …”

Association of theMDM2SNP285 Polymorphism with Cancer Susceptibility: A Meta-Analysis

“…After rigorous assessment of abstracts and contents, only 14 publications met the crude inclusion criteria and were subjected for further evaluation. Of these 14 publications, four were excluded for being without detailed data for further evaluation [28–31], and a total of 10 publications met the inclusion criteria [13–22]. Of the 10 publications, one publication [18] with two ethnic groups was separated as two independent studies, two publications [13, 16] with two cancer types were separated as two independent studies, and one publication [21] with four cancer types was also separated as four independent studies.…”