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Association of the germline TP53 R337H mutation with breast cancer in southern Brazil
Juliana G Assump??o, Ana Seidinger, Maria Mastellaro, Raul C Ribeiro, Gerard P Zambetti, Ramapriya Ganti, Kumar Srivastava, Sheila Shurtleff, Deqing Pei, Luiz Zeferino, Rozany M Dufloth, Silvia Brandalise, José Yunes
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-357
Abstract: We conducted a case-control study to determine the prevalence of the R337H mutation by sequencing TP53 exon 10 in 123 women with breast cancer and 223 age- and sex-matched control subjects from southern Brazil. Fisher's test was used to compare the prevalence of the R337H.The R337H mutation was found in three patients but in none of the controls (p = 0.0442). Among the carriers, two had familial history of cancer meeting the Li-Fraumeni-like criteria. Remarkably, tumors in each of these three cases underwent loss of heterozygosity by eliminating the mutant TP53 allele rather than the wild-type allele. Polymorphisms were identified within the TP53 (R72P and Ins16) and MDM2 (SNP309) genes that may further diminish TP53 tumor suppressor activity.These results demonstrate that the R337H mutation can significantly increase the risk of breast cancer in carriers, which likely depends on additional cooperating genetic factors. These findings are also important for understanding how low-penetrant mutant TP53 alleles can differentially influence tumor susceptibility.Mutations in the TP53 tumor supressor gene usually occur within the highly conserved DNA-binding domain (aa 100–298) and, when inherited, are typically associated with Li-Fraumeni syndrome (LFS), in which carriers develop a broad spectrum of cancers (e.g., breast, brain, soft tissue, bone, blood, and adrenal cortex tumors) during childhood or young adulthood [1]. Families with incomplete features of LFS are referred to as having Li-Fraumeni-like (LFL) syndrome [2,3].In southern Brazil, a unique germline TP53 point mutation resulting in an Arg to His amino acid substitution (R337H) within the C-terminal oligomerization domain is strongly associated with childhood adrenocortical tumors (ACT) [4-6]. Unlike the protypical DNA binding mutants, p53-R337H retains significant activity, although its thermal stability is reduced and it is highly sensitive to slight changes in pH [7]. The R337H mutation has a low overall mal
TP53 and MDM2 Gene Polymorphisms, Gene-Gene Interaction, and Hepatocellular Carcinoma Risk: Evidence from an Updated Meta-Analysis  [PDF]
Qiliu Peng, Xianjun Lao, Zhiping Chen, Hao Lai, Yan Deng, Jian Wang, Cuiju Mo, Jingzhe Sui, Junrong Wu, Limin Zhai, Shi Yang, Xue Qin, Shan Li
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082773
Abstract: Background The association between TP53 R72P and/or MDM2 SNP309 polymorphisms and hepatocellular carcinoma (HCC) risk has been widely reported, but results were inconsistent. To clarify the effects of these polymorphisms on HCC risk, an updated meta-analysis of all available studies was conducted. Methods Eligible articles were identified by search of databases including PubMed, Cochrane Library, EMBASE and Chinese Biomedical Literature database (CBM) for the period up to July 2013. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity. Results Finally, a total of 10 studies including 2,243 cases and 3,615 controls were available for MDM2 SNP309 polymorphism and 14 studies containing 4,855 cases and 6,630 controls were included for TP53 R72P polymorphism. With respect to MDM2 SNP309 polymorphism, significantly increased HCC risk was found in the overall population. In subgroup analysis by ethnicity and hepatitis virus infection status, significantly increased HCC risk was found in Asians, Caucasians, Africans, and HCV positive patients. With respect to TP53 R72P polymorphism, no significant association with HCC risk was observed in the overall and subgroup analyses. In the MDM2 SNP309–TP53 R72P interaction analysis, we found that subjects with MDM2 309TT and TP53 Pro/Pro genotype, MDM2 309 TG and TP53 Arg/Pro genotype, and MDM2 309 GG and TP53 Pro/Pro genotype were associated with significantly increased risk of developing HCC as compared with the reference MDM2 309TT and TP53 Arg/Arg genotype. Conclusions We concluded that MDM2 SNP309 polymorphism may play an important role in the carcinogenesis of HCC. In addition, our findings further suggest that the combination of MDM2 SNP 309 and TP53 Arg72Pro genotypes confers higher risk to develop HCC. Further large and well-designed studies are needed to confirm this association.
Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel  [PDF]
Ranjan Chrisanthar,Stian Knappskog,Erik L?kkevik,Gun Anker,Bj?rn ?stenstad,Steinar Lundgren,Terje Risberg,Ingvil Mjaaland,Gudbrand Skj?nsberg,Turid Aas,Ellen Schlichting,Hans E. Fj?sne,Arne Nysted,Johan Richard Lillehaug,Per Eystein L?nning
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019249
Abstract: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy.
Low Prevalence of TP53 Mutations and MDM2 Amplifications in Pediatric Rhabdomyosarcoma  [PDF]
Simona Ognjanovic,Ghyslaine Martel,Carlos Manivel,Magali Olivier,Erica Langer,Pierre Hainaut
Sarcoma , 2012, DOI: 10.1155/2012/492086
Abstract: The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. The reported prevalence of mutations in rhabdomyosarcoma (RMS) varies widely, with recent larger studies suggesting that TP53 mutations in pediatric RMS may be extremely rare. Overexpression of MDM2 also attenuates p53 function. We have performed TP53 mutation/MDM2 amplification analyses in the largest series analyzed thus far, including DNA isolated from 37 alveolar and 38 embryonal RMS tumor samples obtained from the Cooperative Human Tissue Network (CHTN). Available samples were frozen tumor tissues (=48) and histopathology slides. TP53 mutations in exons 4–9 were analyzed by direct sequencing in all samples, and MDM2 amplification analysis was performed by differential PCR on a subset of 22 samples. We found only one sample (1/75, 1.3%) carrying a TP53 mutation at codon 259 (p.D259Y) and no MDM2 amplification. Two SNPs in the TP53 pathway, associated with accelerated tumor onset in germline TP53 mutation carriers, (TP53 SNP72 (rs no. 1042522) and MDM2 SNP309 (rs no. 2279744)), were not found to confer earlier tumor onset. In conclusion, we confirm the extremely low prevalence of TP53 mutations/MDM2 amplifications in pediatric RMS (1.33% and 0%, respectively). The possible inactivation of p53 function by other mechanisms thus remains to be elucidated.
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
Evidence for an Epistatic Effect between TP53 R72P and MDM2 T309G SNPs in HIV Infection: A Cross-Sectional Study in Women from South Brazil  [PDF]
Fernando Pires Hartwig, Ludmila Gon?alves Entiauspe, Emily Montosa Nunes, Fernanda Martins Rodrigues, Tiago Collares, Fabiana K?mmling Seixas, Mariangela Freitas da Silveira
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089489
Abstract: Objective To investigate the associations of TP53 R72P and MDM2 T309G SNPs with HPV infection status, HPV oncogenic risk and HIV infection status. Design Cross-sectional study combining two groups (150 HIV-negative and 100 HIV-positive) of women. Methods Data was collected using a closed questionnaire. DNA was extracted from cervical samples. HPV infection status was determined by nested-PCR, and HPV oncogenic risk group by Sanger sequencing. Both SNPS were genotyped by PCR-RFLP. Crude and adjusted associations involving each exposure (R72P and T309G SNPs, as well as 13 models of epistasis) and each outcome (HPV status, HPV oncogenic risk group and HIV infection) were assessed using logistic regression. Results R72P SNP was protectively associated with HPV status (overdominant model), as well as T309G SNP with HPV oncogenic risk (strongest in the overdominant model). No epistatic model was associated with HPV status, but a dominant (R72P over T309G) protective epistatic effect was observed for HPV oncogenic risk. HIV status was strongly associated (risk factor) with different epistatic models, especially in models based on a visual inspection of the results. Moreover, HIV status was evidenced to be an effect mediator of the associations involving HPV oncogenic risk. Conclusions We found evidence for a role of R72P and T309G SNPs in HPV status and HPV oncogenic risk (respectively), and strong associations were found for an epistatic effect in HIV status. Prospective studies in larger samples are warranted to validate our findings, which point to a novel role of these SNPs in HIV infection.
Low Prevalence of TP53 Mutations and MDM2 Amplifications in Pediatric Rhabdomyosarcoma  [PDF]
Simona Ognjanovic,Ghyslaine Martel,Carlos Manivel,Magali Olivier,Erica Langer,Pierre Hainaut
Sarcoma , 2012, DOI: 10.1155/2012/492086
Abstract: The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. The reported prevalence of mutations in rhabdomyosarcoma (RMS) varies widely, with recent larger studies suggesting that TP53 mutations in pediatric RMS may be extremely rare. Overexpression of MDM2 also attenuates p53 function. We have performed TP53 mutation/MDM2 amplification analyses in the largest series analyzed thus far, including DNA isolated from 37 alveolar and 38 embryonal RMS tumor samples obtained from the Cooperative Human Tissue Network (CHTN). Available samples were frozen tumor tissues ( ) and histopathology slides. TP53 mutations in exons 4–9 were analyzed by direct sequencing in all samples, and MDM2 amplification analysis was performed by differential PCR on a subset of 22 samples. We found only one sample (1/75, 1.3%) carrying a TP53 mutation at codon 259 (p.D259Y) and no MDM2 amplification. Two SNPs in the TP53 pathway, associated with accelerated tumor onset in germline TP53 mutation carriers, (TP53 SNP72 (rs no. 1042522) and MDM2 SNP309 (rs no. 2279744)), were not found to confer earlier tumor onset. In conclusion, we confirm the extremely low prevalence of TP53 mutations/MDM2 amplifications in pediatric RMS (1.33% and 0%, respectively). The possible inactivation of p53 function by other mechanisms thus remains to be elucidated. 1. Introduction Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma diagnosed in children under the age of 15 years contributing to approximately 4% of all childhood malignancies [1]. Two major subtypes, embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS), together comprise 80% of all rhabdomyosarcoma [2]. The predominant subtype is ERMS which is characterized by earlier age of onset and better survival compared to ARMS (70% versus 50%, resp.) [2, 3]. While ERMS is characterized by frequent loss of imprinting on chromosome 11p15, a region containing a number of imprinted genes, including IGF2, 80% of ARMS present with translocations, most frequently involving PAX 3 or 7 and FOXO gene rearrangements [4, 5]. Young age of onset, a number of identified predisposing syndromes, and paucity of environmental and lifestyle risk factors all contribute to the widely accepted view that genetic aberrations may play an important role in RMS development [3, 5]. However, the etiology of RMS remains largely unknown primarily due to its rarity and diagnostic diversity [2]. TP53 is the most commonly mutated gene in human cancer; however, the prevalence of TP53 mutations varies greatly by cancer type [6]. This tumor
Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers
Ellen R Copson, Helen E White, Jeremy P Blaydes, David O Robinson, Peter W Johnson, Diana M Eccles
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-80
Abstract: Genomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technology? was used to determine the genotype at the MDM2 SNP309 locus.The polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6%) and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G). Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T) individuals (72.7% vs. 75.6%, p = 1.00). Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80).We found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1.Inheritance of a truncating mutation of the breast cancer predisposition gene BRCA1 has been reported to carry a lifetime risk of breast cancer of between 50 and 80%, with age at onset of first malignancy varying from the 2nd to the 8th decade [1,2]. Clinical studies indicate that BRCA1 mutation carriers can benefit significantly from preventative surgery, with prophylactic oophorectomy reducing breast cancer rates by up to 60% and ovarian cancer rates by 95%, and prophylactic double mastectomy reducing the incidence of breast cancer by up to 90% [3,4]. These two interventions are however major surgical procedures with potentially significant psychological and medical sequelae. The ability to predict whether a BRCA1 mutation carrier is likely to develop malignant disease early or late in life would facilitate the clinical management of these patients.No differences in penetrance have yet been documented for different BRCA1 truncating mutations [2]. Inter-individual variation in the speed at which BRCA1 mutation carriers develop cancer is likely to be influenced by environmental factors, but may also be affected by co-inheritance of othe
Association of TP53 codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients
Tatsuya Toyama, Zhenhuan Zhang, Mariko Nishio, Maho Hamaguchi, Naoto Kondo, Hirotaka Iwase, Hiroji Iwata, Satoru Takahashi, Hiroko Yamashita, Yoshitaka Fujii
Breast Cancer Research , 2007, DOI: 10.1186/bcr1682
Abstract: The genotypes of TP53 codon 72 and MDM2 SNP309 were defined among 557 primary Japanese breast cancer patients (median follow-up, 61.7 months). The effects of several variables on survival were tested by Cox's proportional hazards regression analysis.We showed that the Pro/Pro genotype of TP53 codon 72 was associated with poorer disease-free survival (DFS) than other genotypes by Kaplan-Meier analysis (P = 0.049) and multivariate Cox's proportional hazards regression analysis (P = 0.047, risk ratio of recurrence = 1.67), whereas MDM2 SNP309 status was not associated with DFS. The association of the Pro/Pro TP53 genotype with poorer DFS was especially significant in patients who received adjuvant chemotherapy (P = 0.009). In contrast, among the patients who had received adjuvant hormonal therapy or no adjuvant systemic therapy, TP53 codon 72 genotype was not associated with DFS.The Pro/Pro genotype of TP53 codon 72 appears to be an independent prognostic marker in breast cancer patients.The TP53 tumor suppressor pathway is well-known to be crucial for maintaining genomic integrity and preventing cells from undergoing oncogenic transformation [1,2]. MDM2 plays a key role in regulating the TP53 pathway by binding directly to the p53 protein, inhibiting its activity and mediating degradation via the ubiquitination system [3]. p53 also positively regulates MDM2 expression, thereby creating a negative feedback loop [3]. Overexpression of MDM2 is observed both in epithelial cells of transgenic mice with induced mammary carcinomas [4] and in multiple human tumors, including breast cancer [5-7].The TP53 codon 72 Arg>Pro (CGC to CCC) polymorphism of exon 4 [8] (National Center for Biotechnology Information single-nucleotide polymorphism (SNP) identification number rs1042522) has been suggested to play a role in several different cancer types. These two variant protein forms may behave differently, as the Arg/Arg genotype has been reported to induce apoptosis more effectively t
Results based on 124 cases of breast cancer and 97 controls from Taiwan suggest that the single nucleotide polymorphism (SNP309) in the MDM2 gene promoter is associated with earlier onset and increased risk of breast cancer
Ying-Fang Sun, Jyh-Der Leu, Su-Mei Chen, I-Feng Lin, Yi-Jang Lee
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-13
Abstract: Genomic DNA was obtained from the whole blood of 124 breast cancer patients and 97 cancer-free healthy women living in Taiwan. MDM2 SNP309 genotyping was carried out by restriction fragment length polymorphism (RFLP) assay. The multivariate logistic regression and the Kaplan-Meier method were used for analyzing the risk association and significance of age at diagnosis among different MDM2 SNP309 genotypes, respectively.Compared to the TT genotype, an increased risk association with breast cancer was apparent for the GG genotype (OR = 3.05, 95% CI = 1.04 to 8.95), and for the TG genotype (OR = 2.12, 95% CI = 0.90 to 5.00) after adjusting for age, cardiovascular disease/diabetes, oral contraceptive usage, and body mass index, which exhibits significant difference between cases and controls. Furthermore, the average ages at diagnosis for breast cancer patients were 53.6, 52 and 47 years for those harboring TT, TG and GG genotypes, respectively. A significant difference in median age of onset for breast cancer between GG and TT+TG genotypes was obtained by the log-rank test (p = 0.0067).Findings based on the current sample size suggest that the MDM2 SNP309 GG genotype may be associated with both the risk of breast cancer and an earlier age of onset in Taiwanese women.A functional single nucleotide polymorphism has been identified at position 309 within the first intron of the promoter region of the human MDM2 gene and hence designated SNP 309 [1]. Conversion of the T allele to the G allele in the region causes a higher affinity for the Sp1 transcription activator and subsequently enhances the transcription of MDM2 gene. Over-expression of MDM2 oncoprotein may result in a higher risk of carcinogenesis and accelerated tumorigenesis by negatively regulating p53 tumor suppressor protein [2].Supporting evidence for the hypothesis that MDM2 SNP309 influences tumor formation is derived from the clinical outcomes obtained from different research groups. The median age of cancer
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