항목 한글 영문
ID rs4245739
염색체 chr1
염색체상 위치 204518842
표준게놈 유전형 C
위험 유전형 C,A
변이 종류   3_prime_UTR_variant
유전자 MDM4 MDM4
인족별 분포

(A;A) (A;C) (C;C)

관련 표현형 전립선암,유방암 Prostate cancer,Breast cancer

Rs4245739 at 1q32 is located in the 3’ untranslated region (UTR) of MDM4, positioned 32 bp downstream from the gene. The MDM4 oncoprotein negatively regulates the tumor suppressor protein P53, effectively inhibiting apoptosis and promoting cell growth. Amplification of MDM4 is observed in multiple tumor types, and genome-wide association studies (GWAS) have associated SNP rs4245739 with several forms of cancer.

SNPs that are situated in 3’-UTRs can potentially affect translation efficiency by altering miRNA-mediated gene regulation. The rs4245739 A > C polymorphism creates a novel binding site for miR-191 [PMID 21084273], thereby inhibiting expression of the MDM4 oncogene. Consequently, the major allele A acts as the risk allele, while the minor allele C is protective.

Prostate Cancer

A GWAS by Eeles et al. [PMID 23535732OA-icon.png] linked rs4245739 to prostate cancer, a leading cause of cancer-related death for men in the developed world – especially in Europe and the United States. Eeles et al. used the iCOGS chip to genotype 19,662 prostate cancer cases and 19,715 controls, all of European ancestry. The results were subsequently pooled with data from a meta-analysis of 4 previous GWAS covering 11,085 cases and 11,463 controls in populations with European ancestry. The combined results identified 77 loci associated with prostate cancer, which together explain ~30% of the disease’s familial risk. One of the new SNPs identified was rs4245739, which presented genome-wide significance (p = 2.1e-11). The major allele A is the risk allele, with a per-allele odds ratio of 1.10 (95% CI: 1.05 – 1.14). Rs4245739 is correlated with rs1380576(r2 = 0.89), which has been linked to prostate cancer aggressiveness [PMID 20855462OA-icon.png], as well as rs7556371(r2 = 0.89), which was associated with prostate cancer susceptibility in a candidate gene study [PMID 20197460OA-icon.png].

Breast Cancer

Rs4245739 has also been linked to susceptibility for breast cancer, which ranks as the fifth-most common cause of cancer death worldwide. In another GWAS utilizing the iCOGS array, Garcia-Glosas et al. [PMID 23535733OA-icon.png] investigated loci associated with estrogen receptor (ER)-negative tumors, which account for ~25% of all breast cancer cases. They genotyped 6,514 ER-negative breast cancer cases and 41,455 controls of European ancestry, the results of which were combined with a meta-analysis of 3 previous GWAS totaling 4,193 ER-negative cases and 35,194 controls, also of European ancestry. SNP rs4245739 was identified as one of four loci associated with ER-negative but not ER-positive breast cancer. Based on the pooled results, the association with ER-negative breast cancer showed genome-wide significance (p = 2.1e-12). The A risk allele presented an odds ratio of 1.14 (95% CI: 1.10–1.18).

A candidate gene study [PMID 23793604] genotyped a total of 1,100 breast cancer cases and 1,400 controls from two regions of China. This work focused specifically on breast cancer in relation to SNP rs4245739 and its potential interplay with the P53 Arg72Pro genetic variant. When compared to CA and CC, the AA genotype was found to be associated with breast cancer (p = 4.6e-6), with an odds ratio of 0.47 (95% CI: 0.36–0.61) for the C protective allele. For individuals with the P53 Arg/Arg genotype, the association was even stronger (p = 5.3e-12) with an odds ratio of 0.16 (95% CI: 0.08–0.27), suggesting a possible additive effect of MDM4 and P53 on breast cancer susceptibility.

Additionally, smaller scale studies have reported association of rs4245739 with esophageal squamous cell carcinoma [PMID 23724042OA-icon.png] and ovarian cancer severity and progression [PMID 21084273].

관련 논문  

[PMID 23535732] Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.

[PMID 23535733] Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

[PMID 24325915] Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer.

[PMID 18279506] Mutation analysis of the MDM4 gene in German breast cancer patients.

[PMID 23793604] Functional MDM4 rs4245739 genetic variant, alone and in combination with P53 Arg72Pro polymorphism, contributes to breast cancer susceptibility.

[PMID 25670033] A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

[PMID 26274820] A Regulatory MDM4 Genetic Variant Locating in the Binding Sequence of Multiple MicroRNAs Contributes to Susceptibility of Small Cell Lung Cancer

[PMID 26471763] MDM4 SNP34091 (rs4245739) and its effect on breast-, colon-, lung-, and prostate cancer risk

[PMID 26867771] The MDM4 SNP34091 (rs4245739) C-allele is associated with increased risk of ovarian-but not endometrial cancer.

[PMID 28164646] Analysis of the Association between MDM4 rs4245739 Single Nucleotide Polymorphism and Breast Cancer Susceptibility.

[PMID 28547953] Lack of Associations of the MDM4 rs4245739 Polymorphism with Risk of Thyroid Cancer among Iranian-Azeri Patients: a Case-Control Study

비고 표준게놈은 hg19 기준입니다.