Polymorphisms in TP53 and MDM2 combined are associated with high grade endometrial cancer.
OBJECTIVE
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.
Ashton
Katie A
KA
Discipline of Medical Genetics, School of Biomedical Sciences, Faculty of Health, University of Newcastle, Australia.
Proietto
Anthony
A
Otton
Geoffrey
G
Symonds
Ian
I
McEvoy
Mark
M
Attia
John
J
Gilbert
Michael
M
Hamann
Ute
U
Scott
Rodney J
RJ
D016022:Case-Control Studies; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D016158:Genes, p53; D006239:Haplotypes; D006801:Humans; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016019:Survival Analysis
C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2