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Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations
Hovav Nechushtan, Tamar Hamburger, Susan Mendelson, Luna Kadouri, Nir Sharon, Eli Pikarsky, Tamar Peretz
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-60
Abstract: DNA from breast cancer patients was obtained for analysis of one of the three common BRCA1/2 mutations and MDM2 SNP309. Data regarding cancer onset and death ages was obtained from our database and Statistical analysis was performed using the SPSS? statistical package (SPCC Inc., Chicago, IL), and JMP? software (SAS Institute, Cary, NC).The percentage of MDM2 SNP309 in control and BRCA 1/2 population which is similar to that reported for other Jewish Ashkenazi populations at 52.2% for the heterozygotes and 25.0% for MDM2SNP309G/G and 22.8% for MDM2SNP309T/T.There was not a statistical significant difference in median age of disease onset in the different MDM2 SNP309 subgroups of the BRCA1/2 carriers. When we further divided the group into under and above 51 years old ( presumed menopause age) in the BRCA1 positive subset we found that there were less patients of the MDM2SNP309 G/G versus the MDM2SNP309 T/T in the over 51 patient group (p = 0.049). This result has been obtained in a relatively small subgroup and is of borderline statistical significance. Interestingly, in the BRCA1/2 mutation carriers, we found a survival advantage for patients harboring the SNP309 G/G genotype (p = 0.0086) but not for the 272 patients not harbouring this mutations.MDM2SNP309G/G main effect on BRCA1/2 positive mutation carriers is linked to its effect on patients survival. Further research is needed in order to understand the reason for this difference.MDM2 regulates p53 by targeting its destruction through the ubiquitin pathway and also by directly blocking p53 transcriptional activity[1]. A single nucleotide polymorphism (SNP) in the MDM2 promoter (SNP309) was identified [2]. Homozygotic SNP309 G/G carriers express higher levels of MDM2, which can subsequently attenuate the p53 pathway [2]. A significantly reduced age of onset for several p53 dependent cancers have been described in SNP309 G/G homozygous carriers including patients with Li-Fraumeni syndrome [2]. In contrast, studie
Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers  [cached]
Bj?rnslett Merete,Knappskog Stian,L?nning Per,D?rum Anne
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-454
Abstract: Background While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer. Methods 221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465). Results The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005). In contrast, the SNP285C allele reduced risk of BRCA1 related ovarian cancer in carriers of the SNP309G allele (OR 0.50; CI 0.24-1.04; p = 0.057). Censoring individuals carrying the SNP285C/309G haplotype from the analysis elevated the OR related to the SNP309G allele (OR 1.73; CI 1.23-2.45; p = 0.002). The mean age at disease onset was 3.1 years earlier in carriers of SNP309TG+GG as compared to carriers of SNP309TT (p = 0.068). No such associations were found in BRCA2 related ovarian cancer. Conclusions Our results indicate the SNP309G allele to increase and the SNP285C allele to reduce the risk of BRCA1 related ovarian cancer. If confirmed in independent studies, this finding may have implications to counseling and decision-making regarding risk reducing measures in BRCA1 mutation carriers.
Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2
Anna Mulligan, Fergus J Couch, Daniel Barrowdale, Susan M Domchek, Diana Eccles, Heli Nevanlinna, Susan J Ramus, Mark Robson, Mark Sherman, Amanda B Spurdle, Barbara Wappenschmidt, Andrew Lee, Lesley McGuffog, Sue Healey, Olga M Sinilnikova, Ramunas Janavicius, Thomas vO Hansen, Finn C Nielsen, Bent Ejlertsen, Ana Osorio, Iván Mu?oz-Repeto, Mercedes Durán, Javier Godino, Maroulio Pertesi, Javier Benítez, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo
Breast Cancer Research , 2011, DOI: 10.1186/bcr3052
Abstract: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.Germline mutations in BRCA1 and BRCA2 confer high risks of breast, ovarian and other cancers [1-3] and account for 15 to 20% of the excess familial risk of breast cancer among first degree relatives [4,5]. Breast cancer risks for BRCA1 and BRCA2 mutation carriers have been estimated to range between 40 and 87% by age 70 [6-12] with population-based estimates tending to be lowe
Effect of MDM2 SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among non-smoking Chinese women in Singapore
Hui Chua, Daniel Ng, Serena Choo, San Lum, Huihua Li, Li Soh, Kanaga Sabapathy, Adeline Seow
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-88
Abstract: We therefore examined the role of the SNPs in the p53 pathway (p53 codon 72 and MDM2 SNP309) on lung cancer risk and prognosis of a life-time non-smoking female Chinese population, in a hospital-based case-control study of 123 cases and 159 age-matched controls, by PCR analysis.Our findings reveal that the risk of lung cancer among individuals with the MDM2 SNP309 TT genotype was 2.1 (95% CI 1.01-4.36) relative to the GG genotype, contrary to initial expectations that the GG genotype with elevated MDM2 levels will increase cancer risk. Those who had this genotype in combination with the p53 Pro allele had a risk of 2.5 (95% CI 1.2-5.0). There was however no effect of either polymorphism on age at diagnosis of lung cancer or on overall survival.The results thus demonstrate that the MDM2 SNP309 TT rather than the GG genotype is associated with increased risk of lung cancer in this population, suggesting that other mechanisms independent of increased MDM2 levels can influence cancer susceptibility.The TP53 tumour suppressor pathway plays a critical role in cell cycle regulation and apoptosis in many cancers, including lung carcinomas [1], and variation in the genes that regulate this pathway may exert an important influence on tumour development, and hence, cancer risk. Recent interest has focused on the murine double minute-2 protein (MDM2), a nuclear phospoprotein that inhibits p53 activity by promoting its degradation [2]. A single nucleotide polymorphism (SNP309) in the MDM2 promoter has been found to influence transcription of this gene via a greater affinity for the SP1 transcription factor, and hence, individuals with the GG genotype have higher MDM2 levels leading to attenuation of the p53 pathway [3,4]. This has been especially so in the case of females, due to the involvement of the MDM2 SNP in the estrogen receptor signaling pathway [3].Several epidemiologic studies have evaluated this association with varying results. No overall association between MDM2 SNP
Effects of MDM2, MDM4 and TP53 Codon 72 Polymorphisms on Cancer Risk in a Cohort Study of Carriers of TP53 Germline Mutations  [PDF]
Shenying Fang,Ralf Krahe,Guillermina Lozano,Younghun Han,Wei Chen,Sean M. Post,Baili Zhang,Charmaine D. Wilson,Linda L. Bachinski,Louise C. Strong,Christopher I. Amos
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010813
Abstract: Previous studies have shown that MDM2 SNP309 and p53 codon 72 have modifier effects on germline P53 mutations, but those studies relied on case-only studies with small sample sizes. The impact of MDM4 polymorphism on tumor onset in germline mutation carriers has not previously been studied.
Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients
Marjanka K Schmidt, Johanna Tommiska, Annegien Broeks, Flora E van Leeuwen, Laura J Van't Veer, Paul DP Pharoah, Douglas F Easton, Mitul Shah, Manjeet Humphreys, Thilo D?rk, Scarlett A Reincke, Rainer Fagerholm, Carl Blomqvist, Heli Nevanlinna
Breast Cancer Research , 2009, DOI: 10.1186/bcr2460
Abstract: We pooled data from four breast cancer cohorts within the Breast Cancer Association Consortium for which both TP53 R72P and MDM2 SNP309 were genotyped and follow-up was available (n = 3,749). Overall and breast cancer-specific survival analyses were performed using Kaplan-Meier analysis and multivariate Cox's proportional hazards regression models.Survival of patients did not differ by carriership of either germ-line variant, R72P (215G>C) or SNP309 (-410G>T) alone. Immunohistochemical p53 staining of the tumor was available for two cohorts (n = 1,109 patients). Survival was worse in patients with p53-positive tumors (n = 301) compared to patients with p53-negative tumors (n = 808); breast cancer-specific survival: HR 1.6 (95% CI 1.2 to 2.1), P = 0.001. Within the patient group with p53-negative tumors, TP53 rare homozygous (CC) carriers had a worse survival than G-allele (GG/GC) carriers; actuarial breast cancer-specific survival 71% versus 80%, P = 0.07; HR 1.8 (1.1 to 3.1), P = 0.03. We also found a differential effect of combinations of the two germ-line variants on overall survival; homozygous carriers of the G-allele in MDM2 had worse survival only within the group of TP53 C-allele carriers; actuarial overall survival (GG versus TT/TG) 64% versus 75%, P = 0.001; HR (GG versus TT) 1.5 (1.1 to 2.0), P = 0.01. We found no evidence for a differential effect of MDM2 SNP309 by p53 protein expression on survival.The TP53 R72P variant may be an independent predictor for survival of patients with p53-negative tumors. The combined effect of TP53 R72P and MDM2 SNP309 on survival is in line with our a priori biologically-supported hypothesis, that is, the role of enhanced DNA repair function of the TP53 Pro-variant, combined with increased expression of the Mdm2 protein, and thus overall attenuation of the p53 pathway in the tumor cells.Breast cancer outcome may be affected by germ-line variants in genes that play a role in DNA damage control and repair such as TP53 (R72P
An Updated Meta-Analysis on the Association of MDM2 SNP309 Polymorphism with Colorectal Cancer Risk  [PDF]
Xue Qin, Qiliu Peng, Weizhong Tang, Xianjun Lao, Zhiping Chen, Hao Lai, Yan Deng, Cuiju Mo, Jingzhe Sui, Junrong Wu, Limin Zhai, Shi Yang, Shan Li, Jinmin Zhao
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076031
Abstract: Background The mouse double minute 2 (MDM2) gene encodes a phosphoprotein that interacts with P53 and negatively regulates its activity. The SNP309 polymorphism (T-G) in the promoter of MDM2 gene has been reported to be associated with enhanced MDM2 expression and tumor development. Studies investigating the association between MDM2 SNP309 polymorphism and colorectal cancer (CRC) risk reported conflicting results. We performed a meta-analysis of all available studies to explore the association of this polymorphism with CRC risk. Methods All studies published up to July 2013 on the association between MDM2 SNP309 polymorphism and CRC risk were identified by searching electronic databases PubMed, EMBASE, and Chinese Biomedical Literature database (CBM) databases. The association between the MDM2 SNP309 polymorphism and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Results A total of 14 case-control studies including 4460 CRC cases and 4828 controls were identified. We did not find a significant association between the MDM2 SNP309 polymorphism and CRC risk in all genetic models in overall population. However, in subgroup analysis by ethnicity, significant associations were found in Asians (TG vs. TT: OR = 1.197, 95% CI = 1.055–1.358, P=0.005; GG+TG vs. TT: OR = 1.246, 95% CI = 1.106–1.404, P=0.000) and Africans. When stratified by HWE in controls, significantly increased risk was also found among the studies consistent with HWE (TG vs. TT: OR = 1.166, 95% CI = 1.037–1.311, P= 0.010). In subgroup analysis according to p53 mutation status, and gender, no any significant association was detected. Conclusions The present meta-analysis suggests that the MDM2 is a candidate gene for CRC susceptibility. The MDM2 SNP309 polymorphism may be a risk factor for CRC in Asians.
Aromatase expression is increased in BRCA1 mutation carriers
Ashwini L Chand, kConFab, Evan R Simpson, Colin D Clyne
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-148
Abstract: We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women.We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts.Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers.The roles of BRCA1 in cellular functions include cell cycle control, protein degradation, DNA damage repair, and transcriptional regulation of its target genes. One of its target genes is aromatase (CYP19A1), the enzyme that catalyses the conversion of C19 steroids into bioactive estrogens [1]. In vitro studies demonstrate the direct binding of BRCA1 to the proximal promoter region of CYP19A1 (promoter II) and as a consequence the repression of transcription [2,3]. Gene silencing of BRCA1 leads to an inability to impair aromatase gene expression and enzyme activity [2-5]. However, whether this leads to aromatase excess in BRCA1 mutation carriers is unknown.This link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in mutation carriers. Given that aromatase is critical in promoting tumour growth and BRCA1 and 2 mutations account for an 80% increased risk in hereditary breast and ovarian cancer development, it is important to investigate the relationship between BRCA1 and aromatase expression in patients.The mechanism with which aromatase exerts its activity in a tissue-specific manner is via transcriptional regulation of multiple promoters on its gene [6].
MDM2 SNP309 rs2279744 Polymorphism and Gastric Cancer Risk: A Meta-Analysis  [PDF]
Yong Ma, Jianmin Bian, Hongyong Cao
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056918
Abstract: Background MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism (SNP) in the MDM2 promoter region SNP309 has been demonstrated to be associated with an increased MDM2 expression and a significantly earlier age of onset of several tumors, including gastric cancer. Several studies were published to evaluate the association between SNP309 and gastric cancer risk. However, the results remain conflicting rather than conclusive. Objective The aim of this study was to assess the association between the MDM2 SNP309 polymorphism and gastric risk. Methods We performed a meta-analysis to investigate this relationship. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. Results Five published case-control studies, including 1,621 gastric cancer cases and 2,639 controls were identified. We found that the MDM2 SNP309 polymorphism was associated with a significantly increased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR = 1.54; 95%CI = 1.04–2.29, and GG versus GT/TT, OR = 1.49, 95%CI = 1.30–1.72). Furthermore, Egger's test did not show any evidence of publication bias (P = 0.799 for GG versus TT). Conclusion Our results suggest that the MDM2 SNP309 polymorphism may be a low-penetrant risk factor for the development of gastric cancer.
MDM2 SNP309, gene-gene interaction, and tumor susceptibility: an updated meta-analysis
Yan Wan, Wei Wu, Zhihua Yin, Peng Guan, Baosen Zhou
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-208
Abstract: To investigate whether currently published epidemiological studies can clarify the potential interaction between MDM2 SNP309 and the functional genetic variant in p53 codon72 (Arg72Pro) and p53 mutation status, we performed a meta-analysis of the risk estimate on 27,813 cases with various tumor types and 30,295 controls.The data we reviewed indicated that variant homozygote 309GG and heterozygote 309TG were associated with a significant increased risk of all tumor types (homozygote comparison: odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.13-1.37; heterozygote comparison: OR = 1.10, 95% CI = 1.03-1.17). We also found that the combination of GG and Pro/Pro, TG and Pro/Pro, GG and Arg/Arg significantly increased the risk of cancer (OR = 3.38, 95% CI = 1.77-6.47; OR = 1.88, 95% CI = 1.26-2.81; OR = 1.96, 95% CI = 1.01-3.78, respectively). In a stratified analysis by tumor location, we also found a significant increased risk in brain, liver, stomach and uterus cancer (OR = 1.47, 95% CI = 1.06-2.03; OR = 2.24, 95%CI = 1.57-3.18; OR = 1.54, 95%CI = 1.04-2.29; OR = 1.34, 95%CI = 1.07-1.29, respectively). However, no association was seen between MDM2 SNP309 and tumor susceptibility in the stratified analysis by p53 mutation status (GG vs TT: OR = 1.17, 95% CI = 0.75-1.82 and TG vs TT: OR = 1.09, 95% CI = 0.89-1.34 for positive p53 mutation status; GG vs TT: OR = 0.95, 95% CI = 0.72-1.25 and TG vs TT: OR = 1.06, 95% CI = 0.85-1.30 for negative p53 mutation status).The analyses indicate that MDM2 SNP309 serves as a tumor susceptibility marker, and that there is an association between MDM2 SNP309 and p53 Arg72Pro regarding tumor susceptibility. Further studies that take into consideration environmental stresses and functional genetic variants in the p53-MDM2-related genes are warranted.The p53 protein is a principal mediator of growth arrest, apoptosis, and senescence in response to an array of cellular damage [1-3]. Various types of stress can induce high levels of
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