| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q15 | {Accelerated tumor formation, susceptibility to} | 614401 | Autosomal dominant | 3 | MDM2 | 164785 |
A number sign (#) is used with this entry because of evidence that susceptibility to accelerated tumor formation is associated with variation in the MDM2 gene (164785) on chromosome 12q15.
Susceptibility to accelerated tumor formation was associated by Bond et al. (2004) with a polymorphism in the MDM2 gene, which Mitchell et al. (1995) had mapped to chromosome 12q14.3-q15.
By screening 50 healthy volunteers, Bond et al. (2004) identified a SNP in the MDM2 promoter, -410T-G (164785.0001), which they called SNP309 (rs2279744) because of its position at the 309th nucleotide of intron 1. SNP309 was present at a relatively high frequency in both the heterozygous state (T/G, 40%) and the homozygous state (G/G, 12%). Bond et al. (2004) showed that SNP309 increased the affinity of the transcriptional activator Sp1 (189906), resulting in higher levels of MDM2 RNA and protein and subsequent attenuation of the p53 (191170) pathway. They demonstrated that SNP309 was associated with accelerated tumor formation in both hereditary and sporadic cancers in humans. Bond et al. (2004) studied 88 individuals who were members of Li-Fraumeni syndrome (LFS1; 151623) families and had germline mutations in 1 allele of p53. The frequency of SNP309 in these individuals was similar to that found in the 50 normal volunteers. Of the 88 individuals in the Li-Fraumeni cohort, 66 were diagnosed with at least 1 cancer at a median age of 22 years old. Those either heterozygous or homozygous for SNP309 developed tumors on average 7 years earlier than those lacking SNP309. To determine whether SNP309 acted upon sporadic tumors as well as genetically altered individuals with a p53 defect, Bond et al. (2004) studied a group of patients who developed sporadic adult soft tissue sarcomas and had no known hereditary cancer predisposition and no known germline p53 mutation. Individuals homozygous for SNP309 were diagnosed on average 12 years earlier than those without SNP309, and the frequency of the SNP309 G allele was greatly increased in those who developed soft tissue sarcomas at a young age. These data demonstrated that SNP309 does not require the presence of an inactivating germline p53 mutation to associate with earlier soft tissue sarcoma formation.
Bougeard et al. (2006) studied the effect of the SNP309 polymorphism and the arg72-to-pro polymorphism of the p53 gene (191170.0005) on cancer risk in 61 French carriers of the p53 germline mutation. The mean age of tumor onset in MDM2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p less than 0.05). For the p53 codon 72 polymorphism, the mean age of tumor onset in arg allele carriers (21.8 years) was also different from that of pro/pro patients (34.4 years, p less than 0.05). Bougeard et al. (2006) also observed a cumulative effect of both polymorphisms because the mean ages of tumor onset in carriers of MDM2 G and p53 arg alleles (16.9 years) and those with the MDM2 T/T and p53 pro/pro genotypes (43 years) were clearly different (p less than 0.02). Therefore, the results confirmed the impact of the MDM2 SNP309 G allele on the age of tumor onset in germline p53 mutation carriers, and suggested that this effect may be amplified by the p53 arg72 allele. Polymorphisms affecting p53 degradation therefore represent one of the few examples of modifier genetic factors identified to that time in mendelian predispositions to cancer.
In 25 Dutch and 11 Finnish p53 mutation carriers, Ruijs et al. (2007) observed a significantly earlier age of tumor onset in SNP309 G allele carriers versus those homozygous for the T allele (mean difference, 16 years earlier; p = 0.005), confirming previously reported results. In 72 Dutch p53-negative LFS and LFS-related patients, no difference was seen in the age of tumor onset, but there was a significantly higher percentage of SNP309 G/G homozygotes than in the general population (p = 0.02). Ruijs et al. (2007) suggested that the MDM2 SNP309 G allele contributes to cancer susceptibility in LFS and LFS-related families.
Bond, G. L., Hu, W., Bond, E. E., Robins, H., Lutzker, S. G., Arva, N. C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., Onel, K., Yip, L., Hwang, S.-J., Strong, L. C., Lozano, G., Levine, A. J. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119: 591-602, 2004. [PubMed: 15550242] [Full Text: https://doi.org/10.1016/j.cell.2004.11.022]
Bougeard, G., Baert-Desurmont, S., Tournier, I., Vasseur, S., Martin, C., Brugieres, L., Chompret, A., Bressac-de Paillerets, B., Stoppa-Lyonnet, D., Bonaiti-Pellie, C., Frebourg, T. Impact of the MDM2 SNP309 and p53 arg72-to-pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. (Letter) J. Med. Genet. 43: 531-533, 2006. [PubMed: 16258005] [Full Text: https://doi.org/10.1136/jmg.2005.037952]
Mitchell, E. L. D., White, G. R. M., Santibanez-Koref, M. F., Varley, J. M., Heighway, J. Mapping of gene loci in the q13-q15 region of chromosome 12. Chromosome Res. 3: 261-262, 1995. [PubMed: 7606365] [Full Text: https://doi.org/10.1007/BF00713052]
Ruijs, M. W. G., Schmidt, M. K., Nevanlinna, H., Tommiska, J., Aittomaki, K., Pruntel, R., Verhoef, S., van't Veer, L. J. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Europ. J. Hum. Genet. 15: 110-114, 2007. [PubMed: 17003841] [Full Text: https://doi.org/10.1038/sj.ejhg.5201715]