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TP53和MDM2基因的联合多态性与高级别子宫内膜癌相关。

Polymorphisms in TP53 and MDM2 combined are associated with high grade endometrial cancer.

作者信息

Ashton Katie A, Proietto Anthony, Otton Geoffrey, Symonds Ian, McEvoy Mark, Attia John, Gilbert Michael, Hamann Ute, Scott Rodney J

机构信息

Discipline of Medical Genetics, School of Biomedical Sciences, Faculty of Health, University of Newcastle, Australia.

出版信息

Gynecol Oncol. 2009 Apr;113(1):109-14. doi: 10.1016/j.ygyno.2008.12.036. Epub 2009 Feb 3.

Abstract

OBJECTIVES

Determinants of endometrial cancer grade have not been precisely defined, however, cell cycle control is considered to be integrally involved in endometrial cancer development. TP53 and MDM2 are essential components for cell cycle arrest and apoptosis. Polymorphisms in these genes cause TP53 inactivation and MDM2 over-expression, leading to accumulation of genetic errors.

METHODS

One polymorphism in MDM2, rs2279744 (SNP309) and three polymorphisms in TP53 rs1042522 (R72P), rs17878362 and rs1625895 were genotyped in 191 endometrial cancer cases and 291 controls using PCR-based fragment analysis, RFLP analysis and real-time PCR.

RESULTS

The results showed no associations of the three TP53 polymorphisms and MDM2 SNP309 alone or in combination with endometrial cancer risk. However, the combination of MDM2 SNP309 and the three TP53 polymorphisms was significantly associated with a higher grade of endometrial cancer (wild-type genotypes versus variant genotypes: OR 4.15, 95% CI 1.82-9.46, p=0.0003). Analysis of family history of breast cancer revealed that the variant genotypes of the three TP53 polymorphisms were significantly related to a higher frequency of family members with breast cancer in comparison to endometrial cancer cases without a family history of breast cancer (wild-type genotypes versus variant genotypes: OR 2.78, 95% CI 1.36-5.67, p=0.004).

CONCLUSIONS

The combination of the MDM2 SNP309 and the three TP53 polymorphisms appear to be related to a higher grade of endometrial cancer. The association of the endometrial cancer cases with family history of breast cancer and the three TP53 polymorphisms suggests that this constellation of malignancies may represent a low-risk familial cancer grouping.

摘要

目的

子宫内膜癌分级的决定因素尚未明确界定,然而,细胞周期调控被认为与子宫内膜癌的发生密切相关。TP53和MDM2是细胞周期停滞和凋亡的关键成分。这些基因的多态性会导致TP53失活和MDM2过表达,从而导致遗传错误的积累。

方法

采用基于PCR的片段分析、限制性片段长度多态性分析(RFLP分析)和实时PCR技术,对191例子宫内膜癌病例和291例对照进行MDM2基因的一个多态性位点rs2279744(SNP309)以及TP53基因的三个多态性位点rs1042522(R72P)、rs17878362和rs1625895的基因分型。

结果

结果显示,三个TP53多态性位点以及MDM2的SNP309单独或联合起来与子宫内膜癌风险均无关联。然而,MDM2的SNP309与三个TP53多态性位点的联合与较高分级的子宫内膜癌显著相关(野生型基因型与变异型基因型:比值比4.15,95%置信区间1.82 - 9.46,p = 0.0003)。对乳腺癌家族史的分析显示,与无乳腺癌家族史的子宫内膜癌病例相比,三个TP53多态性位点的变异型基因型与乳腺癌家族成员的较高频率显著相关(野生型基因型与变异型基因型:比值比2.78,95%置信区间1.36 - 5.67,p = 0.004)。

结论

MDM2的SNP309与三个TP53多态性位点的联合似乎与较高分级的子宫内膜癌相关。子宫内膜癌病例与乳腺癌家族史以及三个TP53多态性位点的关联表明,这种恶性肿瘤组合可能代表一种低风险的家族性癌症分组。

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