Dataset Information

Murine Double-Minute 2 Homolog Single Nucleotide Polymorphisms 285 and 309 in Cervical Carcinogenesis.

ABSTRACT: In Caucasians, the MDM2 single nucleotide polymorphism (SNP) 285 G>C (rs117039649) neutralizes the effect of 309 T>G (rs2279744), which increases MDM2 expression and impairs the p53 pathway. In this study, we examined the distribution of these two SNPs in Polish women with squamous cell carcinoma (SCC) (n = 379), adenocarcinoma (n = 59) and other cervical tumor types (n = 18).The polymerase chain reaction-restriction fragment length polymorphism technique and DNA sequencing were employed in our study.The P trend value calculated for the MDM2 285 G>C polymorphism was statistically significant (P trend = 0.016) for SCC. Using logistical regression analysis adjusted for the effect of age, pregnancy, oral contraceptive use, tobacco smoking, and menopausal status, we observed that the MDM2 285 G>C SNP protected against SCC, with an adjusted odd ratio (OR) for the C carriers versus G/G genotype of 0.536 (P = 0.019). Stratified analyses of MDM2 285 G>C revealed a protective role of the C allele against SCC in women with a positive history of oral contraceptive use (age-adjusted OR 0.413, P = 0.021) and in premenopausal women (age-adjusted OR 0.362, P = 0.022). We also found that the 285GG/309GG vs 285GG/309 TT genotype increased the risk of SCC (adjusted OR 1.890, P = 0.005). However, the 285CC/309GG + 285GC/309GG versus 285GG/309GG genotype reduced the risk of SCC (adjusted OR 0.311, P = 0.004).Our results demonstrate that the MDM2 285C gene variant and 285CC/309GG + 285GC/309GG genotypes protect against SCC, most likely by neutralizing the effect of the 309 T>G SNP. The 285GG/309GG genotype increases the risk of SCC possibly due to increased MDM2 expression.

SUBMITTER: Roszak A

PROVIDER: S-EPMC4529876 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Murine Double-Minute 2 Homolog Single Nucleotide Polymorphisms 285 and 309 in Cervical Carcinogenesis.

Roszak Andrzej A Misztal Matthew M Sowińska Anna A Jagodziński Pawel P PP

Molecular diagnosis & therapy 20150801 4

<h4>Background and objective</h4>In Caucasians, the MDM2 single nucleotide polymorphism (SNP) 285 G>C (rs117039649) neutralizes the effect of 309 T>G (rs2279744), which increases MDM2 expression and impairs the p53 pathway. In this study, we examined the distribution of these two SNPs in Polish women with squamous cell carcinoma (SCC) (n = 379), adenocarcinoma (n = 59) and other cervical tumor types (n = 18).<h4>Methods</h4>The polymerase chain reaction-restriction fragment length polymorphism t ...[more]

PMID: 26224627

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Project description:Deficiency of the tumour suppressor merlin leads to the development of schwannomas, meningiomas and ependymomas occurring spontaneously or as a part of the hereditary disease Neurofibromatosis type 2 (NF2). Merlin loss is also found in a proportion of other cancers like mesothelioma, melanoma, breast cancer and glioblastoma. The tumour suppressor/transcription factor p53 regulates proliferation, survival and differentiation and its deficiency plays a role in the development of many tumours. 53 can be negatively regulated by FAK, PI3K/AKT and MDM2 and possibly positively regulated by merlin in different cell lines. In this study we investigated the role of p53 in merlin-deficient tumours. Using our in vitro model of primary human schwannoma cells we have previously demonstrated that FAK is overexpressed/activated and localises into the nucleus of schwannoma cells increasing proliferation. AKT is strongly activated via platelet-derived growth factor (PDGF) - and insulin-like growth factor 1 (IGF1) - receptors increasing survival. Here we investigated p53 regulation and its role in proliferation and survival of human primary schwannoma cells using western blotting, immunocytochemistry, immunohistochemistry and proliferation, survival and transcription factor assays. In human primary schwannoma cells p53 was found to be downregulated while MDM2 was upregulated leading to increased cell proliferation and survival. p53 is regulated by merlin involving FAK, AKT and MDM2. Merlin reintroduction into schwannoma cells increased p53 levels and activity, and treatment with Nutlin-3, a drug which increases p53 stability by disrupting the p53/MDM2 complex, decreased tumour growth and reduced cell survival. These findings are important to dissect the mechanisms responsible for the development of merlin-deficient tumours and to identify new therapeutic targets. We suggest that Nutlin-3, possibly in combination with FAK or PI3K inhibitors, can be employed as a novel treatment for schwannoma and other merlin-deficient tumours.

Dataset Information

Murine Double-Minute 2 Homolog Single Nucleotide Polymorphisms 285 and 309 in Cervical Carcinogenesis.

Publications

Murine Double-Minute 2 Homolog Single Nucleotide Polymorphisms 285 and 309 in Cervical Carcinogenesis.

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