The MDM2 285G–309G haplotype is associated with an earlier age of tumour onset in patients with Li-Fraumeni syndrome

Abstract

In the Li-Fraumeni syndrome (LFS) resulting from germline TP53 mutations, the MDM2 SNP309G allele has been shown to be associated with an earlier age of tumour onset, however the significance of this association is controversial. The 285C variation, also located in the MDM2 promoter, has been shown to reduce the strength of Sp1 binding to MDM2 promoter, antagonizing the effect of the 309G variation. In this study, we investigated the interaction of the MDM2 SNP285 and 309 in a large series of 195 LFS patients. Although we observed a lower mean age of tumour onset in patients with MDM2 SNP309 T/G or G/G genotype (23.1 years) than in patients with T/T genotype (27.3 years), the difference was not statistically significant. In contrast, patients with the 285-309 G-G haplotype develop tumours 5 years earlier than patients harbouring other haplotypes (p = 0.044). This result shows that the MDM2 285-309 G-G is a higher risk haplotype in patients with germline TP53 mutations. This study confirms that the MDM2 309G variation is deleterious when its effect is not neutralized by the 285C variation and illustrates the interfering effects of SNPs located within a gene acting as modifier factor in a Mendelian disease.

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

“…Despite the limited number of subjects considered and the rarity of SNP285C allele in the population, results described above show a statistically significant prevalence of this allele in the LFS Suggestive patients (Pearson's v 2 , p = 0.017, Table 2). Confirming previous results [12,36], we detected the SNP285C variant only in subjects harbouring the SNP309GG or GT genotyping thus indicating its presence on the SNP309G allele. Then, considering the combined role of MDM2 SNP285 and SNP309, the observed frequencies of the three possible genotype combinations-MDM2 285G-309T, 285G-309G and 285C-309G-in LFS suggestive patients are 24 % (6 out of 25), 60 % (15 out of 25) and 16 % (4 out of 25) respectively, different from those described in a previous study on TP53 mutation carriers [12].…”

“…Confirming previous results [12,36], we detected the SNP285C variant only in subjects harbouring the SNP309GG or GT genotyping thus indicating its presence on the SNP309G allele. Then, considering the combined role of MDM2 SNP285 and SNP309, the observed frequencies of the three possible genotype combinations-MDM2 285G-309T, 285G-309G and 285C-309G-in LFS suggestive patients are 24 % (6 out of 25), 60 % (15 out of 25) and 16 % (4 out of 25) respectively, different from those described in a previous study on TP53 mutation carriers [12]. Their corresponding frequencies in the control population are 81.1 % (77 out of 95), 16.8 % (16 out of 95) and 2.1 % (2 out of 95).To evaluate the neutralizing effect of SNP285C on SNP309G variation [30] we removed patients carrying the SNP309TT genotype and considered the two possible genotype combinations 285G-309G and 285C-309G; according to our results which showed the presence of the MDM2 285G-309G haplotype in 15 patients and in 16 controls (48.4 and 51.6 % respectively) versus the MDM2 285C-309G haplotype detected in 4 patients and 2 controls (66.7 and 33.3 % respectively), we did not attest any significant antagonizing effect of SNP285C allele on the SNP309G variant on the cancer risk (Pearson's v 2 , p = 0.67).…”

“…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. Its role in a TP53 negative population has never been investigated.…”

“…Since 80.95 % (34 out of 42) of patients coming to the attention of the Department of Medical Genetics of Istituto Ortopedico Rizzoli (Bologna, Italy) with a clinical suspect of LFS do not carry a TP53 mutation, we decided to investigate the effect of three SNPs already related to LiFraumeni syndrome: the Pro72Arg polymorphism located in the coding sequence of TP53 [11], the MDM2 SNP309 in the murine double minute 2 (MDM2) gene [11] and the MDM2 SNP285 located in the MDM2 promoter region, 24 bp upstream of the previous polymorphism [12]. The combined effect of these polymorphisms on cancer risk has been already evaluated in previous studies [13,14] taking into account cohorts of patients and groups of LFS subjects with a TP53 germline mutation but, to date, no proper attention has been dedicated to all patients without a causative TP53 mutation.…”

“…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].…”