Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon

Abstract

MDM2 is a key regulator of the p53 tumor suppressor protein and is overexpressed in many human cancers. Two single nucleotide polymorphisms (SNPs) located in the MDM2 intronic promoter (P2) have been found to exert biological function. The Gallele of SNP309T>G; rs2279744 increases MDM2 transcription and has been linked to increased cancer risk. In contrast, the less frequent SNP285G>C; rs117039649, which is in complete linkage disequilibrium with SNP309 (generating a SNP285C/ 309G variant haplotype), has been related to reduced MDM2 transcription and to reduced risk of breast, endometrial and ovarian cancer. In this large population-based case-control study, we genotyped SNP309 and SNP285 in 10,830 individuals, including cases with cancer of the breast (n51,717), colon (n51,532), lung (n51,331) and prostate (n52,501), as well as 3,749 non-cancer controls. We found a slightly reduced risk for lung cancer among individuals harboring the SNP309TG/GG genotypes compared to the SNP309TT genotype (OR5 0.86; CI 5 0.67-0.98), but this association was restricted to women (OR 5 0.77; CI 5 0.63-0.95) and was not present among men (OR 5 0.91; CI 5 0.77-1.08). Consistent with previous findings, we found a reduced risk for breast cancer among individuals carrying the SNP285GC/309GG genotype versus the SNP285GG/ 309GG genotype (OR 5 0.55; CI 5 0.33-0.93). In conclusion, our data support the hypothesis that the effects of both SNP285 and SNP309 status are tissue dependent.

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].…”

The MDM4 SNP34091 (rs4245739) C-allele is associated with increased risk of ovarian—but not endometrial cancer

“…Our findings in the present study are, however, in line with previous studies reporting SNP34091C to be associated with increased risk for triple-negative breast cancer [23, 24], a subclass of breast cancers sharing some mutational features with HGSOC [35]. The tissue-specific effects observed are also in line with the previously observed effect of the MDM2 SNP285G > C; where the C-allele is proposed to reduce the risk for ovarian, endometrial, and breast cancer, but not cancer of the prostate, lung, or colon [15, 28, 36, 37]. Notably, among cell lines registered in Cancer Cell Line Encyclopedia (CCLE–Broad Institute), we found a lower average MDM4 expression level among ovarian—than endometrial cancer cells.…”

“…Notably, there is a substantial difference in the distribution of this SNP between Europeans and Asians with a MAF of 0.26 and 0.05, respectively [38]. This is also the case for the MDM2 promoter SNPs, SNP309, and SNP285: while the SNP309G allele is associated with an increased cancer risk, predominantly, among individuals of Asian ancestry [33, 34], the SNP285C-allele, which is associated with reduced cancer risk, [15, 28, 36], is absent in Asians and may therefore have a confounding effect on SNP309 risk estimates performed in Caucasian populations [39]. Thus, the somewhat variable results regarding MDM4 SNP34091 and cancer risk may also be explained by yet unknown functional SNP (s) that are in linkage disequilibrium (LD) with SNP34091.…”

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

“…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. A total of 10 publications including 16 studies were included in the final meta-analysis (Table 1).…”

“…For those studies [13, 15, 16, 21] that used the same control group, the control numbers were only calculated once in the total number of controls, and overlapped controls and cases were subtracted from the total number. Overall, 16 published studies of 14,573 cases and 9,115 controls were included in the final meta-analysis.…”