Rs2279744

rs2279744, a variant in the promoter of the MDM2 gene and also known as "-410T-G", "SNP309", and "SNP309T>G", has been studied for several years to determine it's role in cancer origin and treatment. The interest primarily stems from the ability of the MDM2 protein to bind to and thereby enhance the degradation of the tumor suppressor protein known as p53. Studies on rs2279744 include:

• rs2279744(G) carriers in individuals with cancer tend to develop such cancers on average 12 years earlier than those lacking this allele, and the frequency of rs2279744(G) was greatly increased in those who developed soft tissue sarcomas at a young age. [PMID 15550242]

• Individuals with one or more rs2279744(G) alleles who are also carriers of the TP53 rs1042522(C) (arg at aa72) SNP tend to develop cancers earlier than rs2279744(T;T) homozygotes who carry the same p53 SNP. [PMID 16258005]

• rs2279744(T;T) individuals who have a mutant p53 (in their tumors) are at an increased risk of death (risk ratio [RR] of death = 2.33, 95% CI = 1.08 to 5.03). Tumor p53 status was not associated with breast cancer survival among rs2279744(G;T) or rs2279744(G;G) genotypes. [PMID 16818855]

• rs2279744 showed no association with nonsmall cell lung cancer risk in a study of 1,787 Caucasian patients. However, a possible association between nonsmoking (G;G) homozygotes and a higher risk of nonsmall cell lung cancer was reported.[PMID 17957785]

• A study in Chinese leukemia patients found that the rs2279744(G) allele was unexpectedly associated with reduced risk.[PMID 18313915]

• Another study concludes that this SNP on its own has little or no effect on the risk of common cancers, but it might modify the time of tumor onset and prognosis. [PMID 17827408]

• rs2279744(G;G) females are at a 2.76x increased risk (CI: 1.06-7.20, p=0.03) for endometrial cancer compared to (G;T) or (T;T) genotypes based on a study of 73 patients and matched controls.[PMID 17123590]

• A study of 148 individuals with advanced nonsmall cell lung cancer (NSCLC) undergoing first-line chemotherapy, such as the irinotecan plus cisplatin regimen, concluded after multivariate analysis that the rs2279744(T;T) genotype was independently predictive for longer survival (HR = 1.742, p = .032).[PMID 18618574]

• The rs2279744(G;G) genotype was associated with high grade breast cancer tumors (with an odds ratio of 1.64, CI:1.06-2.53, p=0.025) and greater nodal involvement (OR=2.51, CI:1.26-4.98, p=0.009), but was not associated with an earlier age of cancer diagnosis or even risk of breast cancer, in a study of ~300 Scottish Caucasian patients.[PMID 18828900]

• Around 300 cases each of melanoma, basal cell carcinoma, and squamous cell carcinoma were studied relative to this SNP. No significant associations were found between rs2279744 and any of these three types of skin cancer. However, compared with the (T;T) genotype, the adjusted odds ratios of having moles on the arms for (G;T) and (G;G) genotypes was 0.92 (CI: 0.78-1.08) and 0.68 (CI: 0.53-0.87), respectively (p, trend, 0.005).[PMID 18814047]

• rs2279744(G;G) women are diagnosed with melanoma 13 years earlier than women who carry one or no G alleles. Note that this SNP does not cause higher risk of melanoma; it affects only the age at diagnosis of melanoma in women and has no effect in men, as reported in the 23andMe blog [Spittoon].

• Odds ratio for (G;G) 3x, for (G;T) 2x, for breast cancer in a study of 124 Taiwanese patients, along with a correlation towards earlier occurence.[PMID 19144119]

• rs117039649, also known as SNP285C, a second MDM2 SNP found on the SNP305G allele (and only in Caucasians), reduces the risk of both ovarian and breast cancer among SNP309G holders (odds ratio 0.74 and 0.79, respectively), compared to SNP309G holders lacking this (second) SNP.[PMID 21316605]

spittoon rs2279744(G) has been associated with earlier onset for some cancers, including soft tissue sarcoma, diffuse large B-cell lymphoma, colorectal cancer, ovarian cancer and non-small cell lung cancer in women, and decreased survival in people with stomach and kidney cancer. But there is evidence for improved survival in women with ovarian cancer who have the G version of this SNP. Paradoxically, higher levels of the MDM2 protein (as would be expected with the G version of SNP rs2279744 shown to lead to earlier melanoma onset in the current study) have been associated with improved survival for melanoma.

• rs2279744 is not associated with SLE in a study of Caucasians, African-Americans, and Asian children and adults.[PMID 19074170]

• [PMID 19193430] rs2279744, rs1042522, rs17878362 and rs1625895 associated with high grade endometrial cancer

[PMID 19521721] Accelerated decline in lung function in cigarette smokers is associated with TP53/MDM2 polymorphisms

[PMID 19707196] The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

[PMID 19751436] Interaction of Helicobacter pylori with Genetic Variants in the MDM2 Promoter, is Associated with Gastric Cancer Susceptibility in Chinese Patients

[PMID 19837266] TP53 R72P and MDM2 SNP309 polymorphisms in modification of childhood acute lymphoblastic leukemia susceptibility

[PMID 20447891] MDM2 promoter polymorphism is associated with increased susceptibility to hepatocellular carcinoma in Turkish population

[PMID 20736372] Human Papillomavirus Seropositivity Synergizes with MDM2 Variants to Increase the Risk of Oral Squamous Cell Carcinoma

[PMID 21051655] MDM2 as a Modifier Gene in Retinoblastoma

[PMID 20587610] Examination of genetic polymorphisms in newborns for signatures of sex-specific prenatal selection

[PMID 21843334] TP53 and MDM2 gene polymorphisms and risk of hepatocellular carcinoma in Italian patients

[PMID 22251423] NAMPT (visfatin) and AKT1 genetic variants associate with myocardial infarction

[PMID 22558411] MDM2 Promoter SNP344T>A (rs1196333) Status Does Not Affect Cancer Risk