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Abstract
The MDM2 promoter region contains several polymorphisms, some of which have been associated with MDM2 expression, cancer risk and age at cancer onset. del1518 (rs3730485) is an indel polymorphism residing in the MDM2 promoter P1 and is in almost complete linkage disequilibrium with the MDM2 promoter P2 polymorphism SNP309T>G (rs2279744). Cancer risk assessments of del1518 have previously been conducted in relatively small Chinese populations only. In this study we assessed the genotype distribution of del1518 among healthy Caucasians, African Americans and Chinese, and we estimated the Odds Ratios (OR) for incident cancer of the breast, colon, lung and prostate (n=7,081) as compared to controls (n=3,749) in a large Caucasian (Norwegian) cohort.We found the genotypes of the del1518 to vary significantly between healthy Caucasians, African-Americans and Chinese (p< 1×10−5). Further, we found a positive association of the del1518 del-allele with risk of colon cancer (dominant model: OR = 1.15; 95 % CI = 1.01 – 1.31). Stratifying according to SNP309 status, this association remained among carriers of the SNP309TG genotype (OR = 1.21; 95 % CI = 1.01 – 1.46), but with no clear association among carriers of the SNP309TT genotype. In conclusion, our findings suggest del1518 to be associated with increased risk of colon cancer.
Highlights
The Mouse Double Minute 2 homolog (MDM2) is a major regulator of the tumor suppressor p53
To assess potential ethnic differences in del1518 distribution, we analyzed a cohort of 300 healthy African-Americans, and performed data mining from previously published del1518 genotyping of Chinese individuals [24, 25, 27,28,29]
Except for five individuals harboring the del1518 del/del – SNP309TG genotype and two individuals harboring the del1518 ins/del – SNP309GG, the del1518 del variant was restricted to individuals carrying the SNP309TT or SNP309TG genotype, and del1518 del/del homozygosity was only seen among individuals carrying the SNP309TT genotype (Table 1; Figure 1B)
Summary
The Mouse Double Minute 2 homolog (MDM2) is a major regulator of the tumor suppressor p53. MDM2 hyperactivity through mechanisms such as gene amplification, increased transcription and enhanced translation is observed in many human cancers harboring wild-type TP53 [5,6,7], and MDM2 overexpression has been suggested to act as an alternative mechanism of p53 inactivation, promoting tumor growth. While multiple single nucleotide polymorphisms (SNPs) have been identified in MDM2 promoter regions, so far, only a few have been assessed with respect to potential biological functions. The same investigators found the SNP309G allele to be associated with early onset of several malignancies among individuals carrying TP53 germline mutations (Li-Fraumeni syndrome) and lower age at diagnosis of estrogen receptor (ER) rich breast cancer among individuals with wild-type TP53 [9, 8]. Subsequent findings, with respect to the influence of SNP309 status on age at cancer onset as well as cancer risk have, been conflicting [10,11,12,13,14,15,16,17]
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