Topoisomerase IIβ Binding Protein 1 c.*229C&gt;T (rs115160714) Gene Polymorphism and Endometrial Cancer Risk

Ewa Forma,Agnieszka Szymczyk,Anna Krześlak,Katarzyna Wójcik-Krowiranda,Paweł Jóźwiak,Magdalena Bryś,Andrzej Bieńkiewicz

doi:10.1007/s12253-013-9737-7

Abstract

TopBP1 (topoisomerase IIβ binding protein 1) protein is involved in DNA replication, DNA damage checkpoint response and transcriptional regulation. In this study we investigated whether alterations in the TopBP1 gene can influence the risk of endometrial cancer. We examined the association between five single nucleotide polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 3′UTR region of the TopBP1 gene and endometrial cancer risk as well as allele-specific gene expression. One hundred twenty-one endometrial cancer patients were genotyped for these SNPs. Allele-specific TopBP1 mRNA and protein expressions were determined by real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with endometrial cancer. Compared to homozygous common allele carriers, heterozygous for the T variant had significantly increased risk of endometrial cancer [adjusted odds ratio (OR) = 5.59, 95 % confidence interval (CI): 1.96–15.91, p = 0.0003]. Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT genotype. There was a significant association between the rs115160714 and tumor grade and FIGO classification. Most carriers of minor allele had a high grade tumors (G3) classified as FIGO III/IV. The results of our study raise a possibility that a genetic variation of TopBP1 may be implicated in the etiology of endometrial cancer.

Highlights

Endometrial cancer is the most common malignancy of the female reproductive tract
TopBP1 has been established as an essential activator of ATR (ATM and RAD3-related) kinase
The minor allele frequencies of rs115160714 were less than 5 %

Summary

Introduction

Endometrial cancer is the most common malignancy of the female reproductive tract. It accounts each year for approximately 142.000 new cases diagnosed worldwide, and for 42.000 deaths. The most characteristic feature of TopBP1 is that it has eight BRCT (BRCA1 C-terminal) domains [4, 5]. These domains are involved in interaction with other proteins as well as in interaction with single and double-stranded DNA [6]. TopBP1 is recruited to DNA breaks and co-localizes with Nbs (Nijmegen breakage syndrome 1), BRCA1 and 53BP1 (p53-binding protein 1) in nuclear foci. ATR plays a crucial role in maintenance of genomic integrity by delaying cell division in the presence of DNA damage or replication stress [7]

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