Polymorphisms in nucleotide excision repair genes and susceptibility to colorectal cancer in the Polish population.

Katarzyna Paszkowska-Szczur,Jan Lubiński,Bohdan Górski,Aniruddh Kashyap,Józef Kładny,Paulina Gapska,Tadeusz Dębniak,Grzegorz Kurzawski,Tomasz Gromowski,Bartłomiej Masojć,Thierry Van De Wetering,Rodney J Scott,Satish Gupta,Dagmara Dymerska,Cezary Cybulski

doi:10.1007/s11033-014-3824-z

Abstract

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. Genetic polymorphisms in XP genes may be associated with a change in DNA repair capacity, which could be associated with colorectal cancer development. We assessed the association between 94 single nucleotide polymorphisms (SNPs) within seven XP genes (XPA–XPG) and the colorectal cancer risk in the Polish population. We genotyped 758 unselected patients with colorectal cancer and 1,841 healthy adults. We found that a significantly decreased risk of colorectal cancer was associated with XPC polymorphism rs2228000_CT genotype (OR 0.59; p < 0.0001) and the rs2228000_TT genotype (OR 0.29; p < 0.0001) compared to the reference genotype (CC). And an increased disease risk was associated with the XPD SNP, rs1799793_AG genotype (OR 1.44, p = 0.018) and rs1799793_AA genotype (OR 3.31, p < 0.0001) compared to the reference genotype. Haplotype analysis within XPC, XPD and XPG revealed haplotypes associated with an altered colorectal cancer risk. Stratified analysis by gender showed differences between the association of three SNPs: XPC rs2228000, XPD rs1799793 and XPD rs238406 in females and males. Association analysis between age of disease onset and polymorphisms in XPD (rs1799793) and XPC (rs2228000) revealed differences in the prevalence of these variants in patients under and over 50 years of age. Our results confirmed that polymorphisms in XPC and XPD may be associated with the risk of colorectal cancer.

Highlights

Colorectal cancer was second most commonly reported malignancy in 2010 in Poland
Genetic polymorphisms in Xeroderma pigmentosum (XP) genes may be associated with a change in DNA repair capacity, which could be associated with colorectal cancer development
Differences in the haplotype structure revealed two that were protective against colorectal cancer and two that were linked to an enhanced risk of disease (Table 4). In this case–control study that included 758 patients with colorectal cancer and 1,841 healthy adults, we found that the XPC rs2228000 (Ala499Val) and the XPD rs1799793 (Asp312Asn-) polymorphisms were significantly associated with an altered colorectal cancer risk

Summary

Introduction

Colorectal cancer was second most commonly reported malignancy in 2010 in Poland. It represented 12.4 % of all diagnosed male and 10.1 % female malignancies, respectively [1]. MSH6, PMS2 [6], DNA base excision repair genes OGG1 [7], MUTYH [8]; and many other common, low-penetrant genetic variants, which together may be associated with colorectal cancer development [9]. Several reports suggest an association between NER genes and colorectal cancer risk [11,12,13,14,15,16] whereas others have indicated no correlation with disease [17,18,19,20,21,22,23]

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