Previous studies have revealed MDM2 promoter P2 SNP variants like SNP309T??G and SNP285G??C to modulate gene transcription and affect cancer risk [10, 11].
In the present study, we explored the impact of a third MDM2 polymorphism, del1518 ins/del, located in promoter P1, on the risk of endometrial and ovarian cancer in a Caucasian population. Similar to what has been previously reported in Han Chinese [24], we confirmed del1518del/ins to be in strong linkage disequilibrium with the SNP309, forming a distinct MDM2 del1518del/SNP309T haplotype [24, 25] with a MAF different from Chinese (MAF?=?0.30) [24].
We did not detect an effect of del1518 status on the risk of endometrial or ovarian cancer in the general population. Howevver, based on previous findings indicating different MDM2 promoter SNPs may act in concert [11] we performed subgroup analyses stratifying individuals with respect to SNP309 genotypes. (Linkage disequilibrium precluded assessment of SNP285 subgroups since all SNP285C-alleles are linked to SNP309G-alleles while del1518 del locates to the SNP309T-allele [23]).
Doing so, we found the del1518 del- allele to be associated with a reduced risk of endometrial but not for ovarian cancer applying a dominant as well as recessive model among individuals harboring the SNP309TT genotype (risk reduction of 36% and 20%, respectively). This finding is in line with previous in vitro luciferase gene reporter assay findings, showing the presence of the del1518 del allele to result in complete abrogation of promoter activity [12]. Lack of effect on ovarian cancer risk is also in accordance with the results from a previous study performed in Chinese individuals [28]. However, other studies have found the del1518 del allele to confer an increased risk for other cancer forms like hepatocellular carcinomas [26] and left sided colon cancer among individuals carrying the SNP309TG genotype [25], as well as increased risk for uterine leiomyomas (non-cancerous growths in the uterus) [27], but no associations to epithelial ovarian cancer, esophageal squamous cell carcinoma, breast, lung or prostate cancer risk [24, 25, 28–30]. Taken together, these findings suggests the del 1518 ins/del variant may have different effects on risk for cancer development in different organs, partly dependent on interactions with other MDM2 SNP variants, similar to what has been observed for promoter variants like SNP309 and SNP285 [11, 17, 21, 32]. Interestingly, both endometrial and ovarian cancer risk has previously been found to be reduced by the SNP285C-allele [11, 21]. Further, the SNP309G-allele has been found to be associated with an increased but also a reduced cancer risk across different tissues [16, 18, 34, 35]. Also the fact that mice carrying the human MDM2 SNP309G allele only displayed elevated MDM2 expression in a few tissues [36] supports the hypothesis that SNP309 may act as a cancer risk factor in distinct tissues only. Thus, our observation of del1518 del variant reducing the risk of endometrial but not ovarian cancer may indicate that this variant is modulating the binding of transcription factors that are differentially expressed in these two tissues.
Given that we previously have found a SNP in the MDM4 3 ‘UTR (SNP34091) to be associated with increased risk of serous, and in particular high grade serous ovarian cancer [31], we performed subgroup analysis based on histology status with respect to del1581. These subgroup analyses did not reveal any histology specific effects of del1518 status, indicating that this variant have no effect on tumor progression.