Association of the MDM2 SNP285 and SNP309 Genetic Variants with the Risk, Age at Onset and Prognosis of Breast Cancer in Central European Women: A Hospital-Based Case-Control Study

Abstract

SNP309T>G (rs2279744) and SNP285G>C (rs117039649) in the MDM2 promoter are thought to have opposite effects on the binding of transcription factor SP1 (specificity protein 1), and consequently on MDM2 expression, p53 levels, cancer risk, age at onset, and prognosis. Here, we genotyped SNP309 and SNP285 in 406 Austrian breast cancer patients and 254 female controls. The SNP309GG genotype was associated with an increased breast cancer risk in p53 negative (OR, 1.82; 95% CI, 1.09–3.03; p = 0.02), but not p53 positive or unselected patients. In contrast, the SNP309TT genotype was associated with an earlier age at onset (TT, 57.0 ± 12.9; TG, 58.6 ± 13.9; GG, 59.7 ± 15.0 years; p = 0.048). 31% of SNP309TT, 26% of TG, and 13% of GG tumors were p53 positive (p = 0.034), indicating a lower selective pressure to mutate TP53 in the presence of the G-allele. Moreover, SNP309TT patients exhibited a shortened metastasis-free survival in multivariable analysis. Censoring carriers of the SNP285C-allele hardly altered the strength of these associations of SNP309, thus challenging the proposed antagonistic function of SNP285C towards SNP309G. The minor SNP285C-allele tended to be non-significantly associated with an increased breast cancer risk and a poor disease-free and metastasis-free survival, which may be bystander effects of its complete linkage disequilibrium with SNP309G. We conclude that the SNP309G-allele attenuates the p53-response and leads to a higher breast cancer risk, but also to a later onset of breast cancer and a trend towards a good prognosis.

The 40bp Indel Polymorphism rs150550023 in the MDM2 Promoter is Associated with Intriguing Shifts in Gene Expression in the p53-MDM2 Regulatory Hub

“…The frequency of the minor Del-allele of rs150550023 (MAF) was 0.399 in breast cancer patients and 0.429 in controls, close to the 0.416 MAF reported for Europeans by the GnomAD Project population database [ 57 ]. We had previously analyzed MDM2 SNP309 (rs2279744) in our study population [ 21 ], and found that it was in a strong linkage disequilibrium with rs150550023 (D’ = 0.925; p < 0.0001), consistent with previous reports [ 30 , 35 , 41 ]. Accordingly, the rs150550023 Del-allele was found almost exclusively in a distinct SNP309T/rs150550023-Del haplotype.…”

“…MDM2 amplification and overexpression occurs mostly in a mutually exclusive manner with TP53 mutation, indicating that it may be one important of presumably several mechanisms of aberrant inactivation of p53 function in TP53 wildtype tumors [ 8 , 9 , 16 ]. Like MDM2 amplification, albeit less pronounced, the G-allele of SNP309 (rs2279744) in MDM2 promoter P2 was also found associated with increased MDM2 expression and a reduced rate of TP53 mutation [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Moreover, most studies in Asian, but not in Caucasian populations found an association of the G-allele of SNP309 with an increased cancer risk [ 24 , 25 , 26 ].…”

“…SNP309 (rs2279744) is situated in promoter P2 in intron 1 of MDM2 , and was shown to affect binding of transcription factor SP1, MDM2 expression, the risk, age at onset, and prognosis of human cancer, as well as p53 levels and the rate of TP53 mutation [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The rationale of the present study is that rs150550023, which is located in the constitutive promoter P1 proximal to exon1 of MDM2 , might have similar biological effects as SNP309.…”

Association Analysis of TP53 rs1042522, MDM2 rs2279744, rs3730485, MDM4 rs4245739 Variants and Acute Myeloid Leukemia Susceptibility, Risk Stratification Scores, and Clinical Features: An Exploratory Study

“…The associations between the investigated MDM2 variants and cancer susceptibility and progression have a scientific substrate, being well known that these variants increase the MDM2 expression and attenuate the TP53 suppressor pathway. Recently, in other types of cancer, the variant genotypes of MDM2 rs2279744 and/or rs3730485 were reported as risk factors for breast cancer but with a trend towards a good prognosis [48], for laryngeal [49], gynecological cancers [50], and in haplotype analysis for papillary thyroid carcinoma [17].…”

Association between TP53 and MDM2 Gene Polymorphisms and Risk of Hepatocellular Carcinoma in Hepatitis C Virus among Egyptian Populations

“…MDM2 protein negatively regulates the P53 tumor suppressor protein, it binds to the N terminal transactivation domain of P53, thereby inhibiting its transcriptional activity and its growth regulatory function, so the MDM2 gene is overexpressed in several human tumors Recently a SNP309 in the promoter region of MDM2 has been shown to be both hereditary and sporadic cancers in humans. Several studies have reported the association between the TP53 codon 72 and MDM2 G variant SNP309 polymorphisms and increased risk for several types of cancer as gastric breast [27], lung [28], and bladder cancers but few evaluated the association of both these polymorphisms in viral-related liver cancer and none in hepatocellular carcinoma from Egyptian patients.…”