MDM2 SNP309 Polymorphism Research Articles

Lack of association between MDM2 SNP309 and TP53 Arg72Pro polymorphisms with clinical outcomes in myelodysplastic syndrome

MDM2/p53 pathway plays an important role in the control of apoptotic and proliferation mechanisms, and alterations in this pathway have been described in myelodysplastic syndromes (MDS). We investigated the frequency of MDM2 SNP309, TP53 Arg72Pro polymorphisms in de novo MDS and the association of these polymorphisms with clinical characteristics. Our results showed that the frequencies of genotypes for MDM2 SNP309 and TP53 Arg72Pro did not differ between MDS and healthy controls and that these polymorphisms were not associated with clinical and laboratory parameters, disease progression and overall survival, suggesting that MDM2 and TP53 polymorphisms are not involved in risk for MDS, or in the clinical and laboratory characteristics of the disease.

Combined effects of MDM2 SNP309 and TP53 R72P polymorphisms, and soy isoflavones on breast cancer risk among Chinese women in Singapore

The MDM2 oncoprotein regulates the p53 pathway and, while functional polymorphisms of the MDM2 and p53 genes have been investigated for association with breast cancer risk, results are largely null or non-conclusive. We have earlier reported that the increased intake of soy isoflavones reduces risk of postmenopausal breast cancer, and experimental studies suggest that dietary isoflavones can down-regulate the expression of the MDM2 oncoprotein. In this study, we investigated the association between the MDM2 SNP309 and TP53 R72P polymorphisms and breast cancer risk using a case-control study of 403 cases and 662 controls nested among 35,303 women in The Singapore Chinese Health Study, a population-based, prospective cohort of middle-aged and elderly men and women who have been continuously followed since 1993. The G allele of the TP53 R72P polymorphism and T allele of the MDM2 SNP309 polymorphism were putative high-risk alleles and exhibited a combined gene-dose-dependent joint effect on breast cancer risk that was more clearly observed in postmenopausal women. Among postmenopausal women, the simultaneous presence of G allele in TP53 and T allele in MDM2 polymorphisms was associated with an odds ratio (OR) of 2.42 [95% confidence interval (CI) 1.06-5.50]. Furthermore, the protective effect of dietary soy isoflavones on postmenopausal breast cancer was mainly confined to women homozygous for the high activity MDM2 allele (GG genotype). In this genetic subgroup, women consuming levels of soy isoflavones above the median level exhibited risk that was half of those with below median intake (OR 0.52; 95% CI 0.28-0.99). Our findings support experimental data implicating combined effects of MDM2 protein and the p53-mediated pathway in breast carcinogenesis, and suggest that soy isoflavones may exert protective effect via down-regulation of the MDM2 protein.

MDM2 SNP309 Polymorphism and Colorectal Cancer Risk: A Meta-analysis

MDM2 is a phosphoprotein that interacts with p53 and inhibits its activity. Recently, a T to G substitution (SNP309) in the promoter of MDM2 was identified and associated with increased MDM2 expression and a significantly earlier age of onset of several tumors, including colorectal cancer. Several studies evaluated the association between SNP309 and colorectal cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. To derive a more precise estimation of association between MDM2 SNP309 and risk of colorectal cancer, we performed a meta-analysis of 3347 colorectal cancer cases and 3102 controls from eight published case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The results suggested that the variant genotype was associated with a significantly increased colorectal cancer risk (GT vs. TT: OR=1.19, 95% CI=1.06-1.35; p=0.005). In the stratified analyses, significantly increased risks were found among Asian populations (OR=1.28, 95% CI=1.10-1.50; p=0.002) and population-based studies (OR=1.18, 95% CI=1.03-1.34; p=0.016). Although some bias could not be eliminated, this meta-analysis suggested that the MDM2 SNP309 polymorphism is a low-penetrance risk factor for the development of colorectal cancer, particularly among Asians.

Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups

The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair "TP53 response pathway". Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis <53 years, n = 295) with gene expression data available. Patients were classified in subgroups according to their tumor TP53 mutation status and three gene expression profiles; a TP53 mutation status expression signature, a PTEN/PI3K pathway signature and the 70-gene prognosis profile. Survival analyses were performed using Cox regression models adjusting for clinico-pathological characteristics and treatment. An increase in breast cancer-specific mortality was observed for carriers of the germline MDM2 SNP309 rare GG-genotype (range hazard ratios: 2-3) or TP53 R72P heterozygous GC-genotype (range hazard ratios: 1-2) compared to those having the common genotypes within subgroups of tumors displaying a "more aggressive phenotype" gene expression profile. There was no evidence of such an effect on survival within the TP53-mutated tumor group for TP53 R72P carriers but a suggestion of an effect for MDM2 SNP309 carriers (GG vs. TT-genotype HR 2.99, P = 0.06). These results indicate that common polymorphisms in specific pathways may add to the worse prognosis of patients with tumors in which these pathways are affected by somatic alterations.

Role of the MDM2 SNP309 polymorphism in the initiation and early age of onset of nasopharyngeal carcinoma

Recent studies refer that amplification/overexpression of the principal negative regulator of p53 (Mdm2) is frequently found in several malignancies. Several studies have associated a polymorphism (SNP309 T/G) in the promoter region of MDM2 with higher levels of this protein, which will favor p53-pathway abolishment, cell-cycle escape, and development of cancer. We aimed to study if MDM2 SNP309 T/G polymorphism contributes to the development of nasopharyngeal carcinoma (NPC). We have developed a case-control study with 124 patients with NPC and 509 healthy individuals from the north of Portugal to determine the genetic distribution of the MDM2 SNP309 polymorphism in DNA extracted from peripheral blood samples. Statistical analysis was performed to compare categorical variables adjusted for age and gender by multivariate logistic regression. Genotype-specific distributions according to age of onset were tested by Kaplan-Meier method and analyzed by Cox-regression proportional hazard model adjusted for gender. This study revealed that MDM2 SNP309 GG homozygous represent an increased risk adjusted for age and gender to develop NPC (OR = 2.15), with particular effect in undifferentiated types (OR = 2.46) and early clinical stages (OR = 3.32). We also found that median age of onset of NPC was significantly different (55.2 vs. 61.6) with increased effect in undifferentiated types (55.2 vs. 61.9) and early clinical stages (55.3 vs. 65.3). Our study suggests that MDM2 SNP309 can be considered a risk marker for the development of NPC mainly in early ages probably as an initiation marker for potential cancer development.

TP53 R72P and MDM2 SNP309 Polymorphisms and Colorectal Cancer Risk: The Fukuoka Colorectal Cancer Study

Tumor protein p53 gene and its negative regulator, murine double minute 2 homolog are important components for cell-cycle arrest and apoptosis. An arginine-to-proline substitution at codon 72 in the p53 gene is reported to decrease apoptotic potential, while a thymine-to-guanine polymorphism at nucleotide 309, named SNP309, of murine double minute 2 gene increases transcription of the gene. These two polymorphisms therefore may be of importance in colorectal carcinogenesis. The relation of these polymorphisms to colorectal cancer risk was addressed in the Fukuoka Colorectal Cancer Study. We genotyped the two polymorphisms in 685 incident cases of colorectal cancer and 778 community controls by the polymerase chain reaction-restriction fragment length polymorphism method. Statistical adjustment was made for sex and age. The proline allele of p53 gene and the guanine allele of SNP309 were each associated with a small, statistically non-significant increase in the odds ratio of colorectal cancer; the adjusted odds ratio (95% confidence interval) for arginine/proline and proline/proline genotypes combined versus arginine/arginine genotype of p53 gene was 1.23 (0.99-1.52) and that for thymine/guanine and guanine/guanine genotypes combined versus thymine/thymine genotype of SNP309 was 1.27 (0.98-1.63). Individuals harboring the proline allele of p53 gene and the guanine allele of SNP309 showed an odds ratio of 1.67 (95% confidence interval, 1.11-2.51). Codon 72 polymorphism of p53 and SNP309 in combination may confer an increased risk of colorectal cancer.

Polymorphisms of p53 codon 72 and MDM2 promoter 309 and the risk of endometrial cancer

Genetic polymorphisms of p53 and its negative regulator murine double minute 2 homolog (MDM2) have been shown to be closely associated with tumorigenesis in a variety of human cancers. In the present study, single nucleotide polymorphism (SNP) at p53 codon 72 and MDM2 promoter 309 was examined for germline DNA samples from 102 endometrial cancer cases and 95 controls using polymerase chain reaction-based fragment analysis. There were no significant differences in the genotype and allele prevalence between control subjects and endometrial cancer patients for p53 codon 72. The GG genotype frequency of MDM2-SNP309 was statistically higher in endometrial cancer patients than that in normal healthy women when compared with the TG genotype (P= 0.0088). However, no statistically significant differences were found between the TT and TG or GG genotype frequencies and allele prevalence. Interestingly, the combination of the homozygous Arg/Arg genotype of p53 codon 72 and homozygous GG genotype of MDM2 SNP309 polymorphisms was significantly associated with the risk of endometrial cancer (odds ratio = 3.28, 95% confidence interval = 1.13 to 9.53, P= 0.0212). The homozygous variants of wild p53 codon 72 and mutant MDM2 promoter 309 may cooperatively increase the risk of endometrial cancer in a Japanese population.

Differential effects of MDM2 SNP309 polymorphism on breast cancer risk along with race: a meta-analysis

MDM2 SNP309 is a single nucleotide T > G polymorphism present in intron 1 of the MDM2 gene. A variety of case-control studies have been published evaluating the association between MDM2 SNP309 and breast cancer risk. However, the published studies, as well as the subsequent meta-analyses, have yielded contradictory results. This meta-analysis aims to examine whether MDM SNP309 polymorphism may exert a differential effect on breast cancer risk along with race. Eligible articles were identified by a search of MEDLINE, Cochrane and EMBASE bibliographical databases for the period July 1993 to June 2009; 16 case-control studies were eligible (12,986 breast cancer cases, 12,993 controls). Subanalyses in case-control studies conducted on Chinese (3 studies, 892 cases, 1,435 controls) and non-Chinese populations (13 studies, 12,094 cases, 11,558 controls) were performed. All pooled odds ratios (ORs) were derived from fixed-effects models given that the between-study heterogeneity was not statistically significant. Subanalysis on Chinese subjects demonstrated that GT and GG genotype were associated with increased breast cancer risk (pooled OR = 1.272, 95% CI 1.025-1.578 and pooled OR = 1.323, 95% CI 1.034-1.694, respectively); as a result the overall effect of the G allele was statistically significant (pooled OR = 1.287, 95% CI 1.048-1.579). On the contrary, no significant associations between MDM2 SNP309 status and breast cancer risk were demonstrated in non-Chinese populations. In conclusion, the association between MDM2 SNP309 and breast cancer is modified by race. MDM2 SNP309 represents a risk factor for breast cancer in Chinese women but not in non-Chinese women. This phenomenon is analogous to that described in the context of lung cancer.

Cigarette Smoking, MDM2 SNP309, Gene–Environment Interactions, and Lung Cancer Risk: A Meta-Analysis

MDM2 SNP309 polymorphism was found to contribute to genetic susceptibility to lung cancer in humans. However, association studies on these polymorphisms in lung cancer cases have shown conflicting results. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratio (OR) with 95% confidence interval (CI) was applied to assess the strength of association between MDM2 SNP309 polymorphism and risk of lung cancer development. The logistic regression indicated that the genetic model was most likely to be recessive. Using a recessive model, the pooled OR estimating the genotype GG against the T-allele carriers (GT + TT) were calculated. Eight studies, including 6063 cases and 6678 controls, were involved in this meta-analysis. Overall meta-analysis indicated that MDM2 SNP309 GG genotypes have an approximate 16% increased risk for lung cancer development with a statistical significance (OR = 1.16; 95% CI: 1.01–1.34). In the subgroup analyses based on ethnicities, no significant elevated risk was associated with MDM2 SNP309 genotypes found in Asian and Europeans. No significant increased risk was associated with MDM2 SNP309 genotypes found in ever smokers. MDM2 SNP309 GG genotype had an approximate 36% enhanced risk of lung cancer development with statistical significance in never smokers (OR = 1.36; 95% CI: 1.10–1.68). Although some bias cannot be excluded, this meta-analysis supports the view that MDM2 SNP309 gene is a low-penetrance susceptible gene in the development of lung cancer, and the relationship of MDM2 SNP309 and lung cancer is stronger for never smokers.

Effect of TP53 Arg72Pro and MDM2 SNP309 Polymorphisms on the Risk of High-Grade Osteosarcoma Development and Survival

The germ-line polymorphisms TP53 Arg72Pro and MDM2 SNP309 T>G are risk factors for tumor development and affect response to chemotherapy and survival in several cancers, but their prognostic and predictive value in patients with high-grade osteosarcomas is not yet defined. The purpose of this study was to investigate the effect of the TP53 Arg72Pro and the MDM2 SNP309 on the risk of osteosarcoma development and survival. The relative risk to develop osteosarcomas and the overall survival associated to TP53 Arg72Pro and MDM2 SNP309 polymorphisms were investigated in 201 patients. Correlations with event-free survival (EFS) were analyzed in a homogeneous subgroup of 130 patients with high-grade osteosarcomas of the limbs, nonmetastatic at diagnosis, which underwent neoadjuvant chemotherapy. Multivariate analysis showed that the MDM2 polymorphism T309G was associated with an increased risk of developing osteosarcomas [GG versus TT; odds ratio, 2.09; 95% confidence interval (95% CI), 1.15-3.78]. A case/control gender approach evidenced a significant increased risk only for female osteosarcoma patients (GG versus TT; odds ratio, 4.26; 95% CI, 1.61-11.25). Subjects carrying the TP53 Arg72Pro polymorphism were found to have a significantly increased death risk (Pro/Pro versus Arg/Arg; hazard ratio, 2.90; 95% CI, 1.28-6.66). In the subgroup of 130 high-grade osteosarcomas, the TP53 Arg72Pro was an independent marker of EFS (Pro/Pro versus Arg/Arg; hazard ratio, 2.67; 95% CI, 1.17-6.11). The study provides evidence supporting the association of MDM2 SNP309 with high-grade osteosarcoma risk in females and shows that TP53 Arg72Pro has a prognostic value for overall survival and EFS in osteosarcoma patients.

Risk of MDM2 SNP309 alone or in combination with the p53 codon 72 polymorphism in acute myeloid leukemia

A single nucleotide polymorphism (SNP) in the promoter of MDM2 gene, SNP309 T>G (a T–G exchange at nucleotide 309 in the first intron), can increase the expression level of MDM2, thereby causing an impairment of p53 tumor suppressor activity. A G–C exchange at p53 codon 72 polymorphism results in a substitution of proline (Pro) for arginine (Arg) in the transactivation domain, which was shown to alter the primary structure of the p53 protein. Both polymorphisms have been implicated in cancer. To investigate whether that MDM2 SNP309 and p53 codon 72 polymorphism should be at least partially responsible for genetic susceptibility to acute myeloid leukemia (AML), both polymorphisms were determined in a case–control study consisting of 231 AML patients and 128 normal individuals. The MDM2 SNP309G allele was associated with increased risk of AML. Furthermore, the p53 codon 72 and MDM2 SNP309 polymorphisms did not associate with age of onset and any other clinical parameters studied. When the p53 and MDM2 polymorphisms were combined, no multiplicative joint effect between the MDM2 GG and p53 Pro/Pro genotypes exists in the risk of developing AML. These results suggest that the MDM2 SNP309 homozygous GG genotype may be a genetic susceptibility factor in the pathogenesis of AML.

MDM2 SNP309 does not confer an increased risk to oral squamous cell carcinoma but may modulate the age of disease onset

The MDM2 SNP309 has been associated with increased expression of the protein which could suppress p53 function, and has been shown to modulate risk to cancer. We have previously shown that overexpression of MDM2 is a common event in oral cancers. In the present study, we determined the association between the MDM2 SNP309 polymorphism and oral cancer in 207 oral cancer patients and 116 normal subjects. We genotyped the MDM2 SNP309 by PCR-RFLP. Logistic regression was adapted to calculate odds ratios for MDM2 SNP309 polymorphism from univariate and multivariable adjusted models. Our results suggest that MDM2 SNP309 does not confer increased risk to oral cancer (OR=1.55, 95% CI=0.77-3.11). However, the GG/TG genotype was associated with later disease onset in women above 55 years of age. Collectively, our data suggests that MDM2 SNP309 may modulate the risk to oral cancer and is a modifier of the age at oral cancer onset in women above the age of 55 years.

Clinical implications of the MDM2 SNP309 and p53 Arg72Pro polymorphisms in transitional cell carcinoma of the bladder

Recent studies have shown that functional polymorphisms at the MDM2 SNP309 T/G and p53 Arg72Pro may be associated with cancer susceptibility. However, the role of these polymorphisms on the risk of transitional cell carcinoma of the bladder (TCCB) and clinical outcome remains unknown. SNP309 and p53 Arg72Pro polymorphisms were genotyped in 227 patients and 266 control subjects. The association between each polymorphism, TCCB risk and clinical outcome was evaluated by using a logistic regression model, a Kaplan-Meier curve with the log-rank test, or a Cox proportional hazard model. No significant associations between the polymorphisms and TCCB risk were found. On the MDM2 SNP309, the TT patients with superficial TCCB tended to have a longer recurrence-free survival than the TG or GG patients after transurethral resection (P=0.074). On the p53 Arg72Pro, the Pro/Pro patients with superficial TCCB had a significantly lower risk for recurrence than the Arg/Pro or Arg/Arg patients [Hazard ratio (HR), 0.364; 95% confidence interval (CI), 0.14-0.93]. In contrast, the Pro/Pro patients following radical cystectomy showed a significantly poorer survival and a higher risk of disease-specific death than the Arg/Pro + Arg/Arg patients (HR, 2.76; 95% CI, 1.11-6.84). MDM2 SNP309 and p53 Arg72Pro polymorphisms might influence the clinical outcome of TCCB in a distinctive way between superficial TCCB and invasive TCCB. The results may reflect marked differences in the genetic background between superficial and an invasive type of TCCB.

Mdm2-SNP309 polymorphism in prostate cancer: no evidence for association with increased risk or histopathological tumour characteristics

The search for inherited cancer susceptibility factors is a major focus of epidemiologic cancer studies. Analyses of single-nucleotide polymorphisms (SNP) in a variety of genes revealed a correlation between a specific allele variant and cancer predisposition. Human mouse double-minute 2 protein (Mdm2) is a cellular E3 ligase capable of ubiquitination and degradation of p53. Therefore, Mdm2 is a crucial factor of cell cycle control and cell survival. The Mdm2 promoter SNP309 was shown to increase Mdm2 expression and can, thereby, inhibit the p53 pathway. This SNP was found to be associated with increased risk and early onset of various malignancies. For prostate cancer no studies are reported to date. In a case–control study we determined the distribution of the Mdm2 SNP309 in 145 male subjects with prostate cancer and in 124 male controls without any malignancy using RFLP analysis. Cases and controls showed a similar distribution of the SNP (P=0.299). Genotype distribution showed neither an association with histopathological characteristics of the tumours nor with prognosis. Age at disease onset was also not modified by the SNP. This first study of the Mdm2 SNP309 in prostate cancer patients suggests no correlation between a certain allelic variant and an increased cancer risk.

A single nucleotide polymorphism in the Mdm2 promoter and risk of sepsis

Background The Mdm2-SNP309(T/G) polymorphism has been shown to upregulate transcription of Mdm2 and subsequently attenuate the p53 pathway. Its role in regulating the human response to acute illness has not been reported. Methods Patients from the surgical intensive care unit were prospectively enrolled. SNP309 genotype was determined, and a genotype-based comparison of clinical outcomes was performed. Results Of the 85 enrolled patients, 41 had wild type (T/T) and 44 had mutant (32 T/G and 12 G/G) genotypes. The mutant-genotype group tended to have a longer LOS in both the surgical intensive care unit ( P = .40) and the hospital ( P = .08), but these trends did not reach significance. No observable genotype-based differences were noted in any other measured parameters. Conclusions The Mdm2-SNP309(G) allele may be associated with longer LOS. However, it does not appear to influence any other clinical characteristics, nor can it be used to predict clinical outcome.

MDM2 SNP309 G allele decreases risk but does not affect onset age or survival of Chinese leukaemia patients

Although mutations in p53 are rare in leukaemia, MDM2, the negative regulator of p53, is often overexpressed. Recently, a single nucleotide polymorphism (SNP) in the MDM2 promoter - within the oestrogen-receptor-binding region - resulting in either a G or T allele was shown to affect its transcription, with elevated MDM2 being produced when it is a G allele. Expectedly, SNP309G females were found to be at a higher risk of accelerated onset of cancers. We have therefore analysed, in a pilot study, whether the status of MDM2 SNP309 and p53 codon-72 polymorphism, which was also shown to affect cancer predisposition, would affect cancer risk, onset age, overall survival and response to therapy in Chinese leukaemia patients. p53 SNP was not associated with any of the parameters. However, in contrast to expectations, the MDM2 SNP309G allele was associated with reduced risk of leukaemia. No other association was found between SNP309 and other parameters in both males and females. Thus, the data highlights ethnic differences in the effects of this SNP on cancer risk.

MDM2 SNP309 Polymorphism as Risk Factor for Susceptibility and Poor Prognosis in Renal Cell Carcinoma

MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism in the MDM2 promoter region SNP309 (rs2279744) has been shown to increase the affinity of the transcriptional activator Sp1, resulting in elevated MDM2 transcription and expression in some cancers. There is currently no information about the role of MDM2 polymorphism in renal cell carcinoma (RCC). We investigated polymorphisms in p53-related genes, including MDM2, and their interactions in renal cancer. We genotyped three single nucleotide polymorphisms of three genes (p53 Arg(72)Pro, p21 Ser(31)Arg, and MDM2 SNP309) in 200 patients with renal cancer and 200 age- and gender-matched healthy subjects. Genotyping was confirmed by direct DNA sequencing. Samples that showed significant polymorphic variants were analyzed for MDM2 expression by immunohistochemistry. Association of polymorphic variants on survival of RCC patients was analyzed by Kaplan-Meier curves. A significant increase in the GG genotype of the MDM2 SNP309 was observed in RCC patients compared with healthy controls (odds ratio, 1.80; 95% confidence interval, 1.14-2.84). To investigate the effect of the MDM2 SNP309 polymorphism on MDM2 expression, immunohistochemistry was done in genotyped RCC tissues. Positive staining for MDM2 was detected in 2 of 15 (13%) TT genotype, 4 of 15 (26%) TG genotype, and 5 of 10 (50%) GG genotype carriers. The frequency of MDM2 expression in GG genotype carriers was significantly higher than that in TT genotype carriers. Polymorphisms of p53 Arg(72)Pro and p21 Ser(31)Arg did not show significant association with RCC. In univariate and multivariate analysis, MDM2 SNP309 GG genotype was independently associated with poor prognosis. Kaplan-Meier curve analysis showed that survival of patients with GG carriers was significantly worse than that of carriers with TG + TT genotypes. This is the first report to show a significant association between functional polymorphisms in MDM2 and increased risk of developing renal cancer. In addition, the MDM2 polymorphism was shown to be an independent adverse prognostic factor for RCC. Patients with MDM2 309GG genotype showed worse prognosis and low survival.

The functional MDM2 SNP309 polymorphism is associated with an earlier age of diagnosis in women with lung cancer

10550 Background: MDM2 protein is a key negative regulator of p53 protein by targeting its destruction through the ubiquitin pathway. A single nucleotide polymorphism (SNP309 T→G) has been identified in the promoter of the MDM2 gene which results in higher levels of MDM2 protein, attenuation of the p53 pathway, and enhanced tumorigenesis. Estrogen signaling has also been shown to upregulate MDM2 expression. Recent studies have suggested that the MDM2 SNP309 polymorphism is associated with earlier age of onset of certain cancers, particularly in women. The purpose of this study was to determine whether the MDM2 SNP309 polymorphism is associated with lung cancer risk in a gender specific manner. Methods: MDM2 genotype analysis was performed on a cohort of 115 consecutive Caucasian patients with histologically confirmed lung cancer using a PCR-based nucleotide polymorphism discrimination test. Allele status was described as homozygous wild-type (TT), homozygous variant (GG) and heterozygous variant/wild-type (TG). Results: In total, 46 female and 69 male lung cancer patients were screened for the MDM2 SNP309 polymorphism ( Table 1 ). Females with the GG genotype were diagnosed at a significantly earlier age as compared to females with the TT genotype (p=0.038), while a similar comparison for males showed no significant difference. A trend towards an earlier age of onset in females as compared to males with the GG genotype was observed, although the sample size was small and this was not significant (p=0.47). Conclusions: In this study, we found that women, but not men, with the MDM2 SNP309 GG genotype were particularly susceptible to the development of lung cancer at an earlier age, supporting the hypothesis that the expression of this polymorphism is gender-specific and possibly regulated by estrogen. Women with the MDM2 polymorphism represent a potential high-risk group for the focus of lung cancer screening and chemoprevention efforts with anti-estrogen therapy. [Table: see text] No significant financial relationships to disclose.

Stage and histology influence the relationship between MDM2 promoter polymorphism and esophageal cancer and overall survival (OS)

21047 Background: A single nucleotide polymorphism in the MDM2 promoter (SNP309) has been found to affect OS of advanced stage gastric adenocarcinoma (AD) and early stage squamous (SQ) cell carcinoma of the lung. The aim of this study was to evaluate the role of this polymorphism in the prognosis of esophageal cancer, another aerodigestive cancer. Methods: 150 early stage (E) and 118 locally advanced stage (LA) esophageal cancers were genotyped for MDM2 SNP309 using Taqman. The primary endpoint was overall survival (OS). Results: E disease: n=23 stage I; n=127 stage II. LA disease: n=93, Stage III; n=25, Stage IVA. AD comprised 215 (81%), while SQ comprised 45 (17%) of cases; 8 (3%) had poorly differentiated tumors. Median follow-up = 32 months. Median OS were 36 and 21 months for E and LA disease, respectively. Both histology and disease stage affected the relationship between SNP309 and esophageal cancer OS (see Table ). The wildtype T/T genotype conferred a worse OS in E patients (log-rank, p=0.03), especially those with AD (log-rank, p=0.003). In Cox proportional hazards interaction analyses, after adjusting for age, gender, stage and PS, there were statistically significant interactions between MDM2 SNP309 and disease stage (interaction p=0.004) and between MDM2 SNP309 and histologic subtype (AD vs. SQ)(interaction p=0.02). Thus, the direction of SNP309 association from our AD and E esophageal cancer patients are opposite to those of our SQ and LA esophageal cancer patients. However, our SQ and LA results are similar to the SQ lung cancer and advanced stage gastric cancers previously reported. This suggests that biologic mechanisms underpinning the prognostic role of SNP309 are dependent on extent of disease and histologic subtype. Conclusion: Histology and disease stage interact with the prognostic role of MDM2 SNP309 polymorphism in esophageal cancer OS. [Table: see text] No significant financial relationships to disclose.

Younger Age of Cancer Initiation Is Associated with Shorter Telomere Length in Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome frequently associated with germ line TP53 mutations. Unpredictable and disparate age of cancer onset is a major challenge in the management of LFS. Genetic modifiers, including the MDM2-SNP309 polymorphism, and genetic anticipation have been suggested as plausible explanations for young age of tumor onset, but the molecular mechanisms for these observations are unknown. We speculated that telomere attrition will increase genomic instability and cause earlier tumor onset in successive generations. We analyzed mean telomere length and MDM2-SNP309 polymorphism status in individuals from multiple LFS families and controls. A total of 45 peripheral blood lymphocyte samples were analyzed from 9 LFS families and 15 controls. High rate of MDM2-SNP309 was found in TP53 carriers (P = 0.0003). In children, telomere length was shorter in carriers affected with cancer than in nonaffected carriers and wild-type controls (P < 0.0001). The same pattern was seen in adults (P = 0.002). Within each family, telomere length was shorter in children with cancer than in their nonaffected siblings and their noncarrier parents. Telomere attrition between children and adults was faster in carriers than in controls. Our results support the role of MDM2-SNP309 as a genetic modifier in LFS. The novel finding of accelerated telomere attrition in LFS suggests that telomere length could explain earlier age of onset in successive generations of the same family with identical TP53/MDM2-SNP309 genotypes. Furthermore, telomere shortening could predict genetic anticipation observed in LFS and may serve as the first rational biological marker for clinical monitoring of these patients.