DNA repair genes polymorphism and lung cancer risk with the emphasis to sex differences

Abstract

Polymorphisms in nucleotide and base excision repair genes are associated with the variability in the risk of developing lung cancer. In the present study, we investigated the polymorphisms of following selected DNA repair genes: XPC (Lys939Gln), XPD (Lys751Gln), hOGG1 (Ser326Cys) and XRCC1 (Arg399Gln), and the risks they present towards the development of lung cancer with the emphasis to gender differences within the Slovak population. We analyzed 761 individuals comprising 382 patients with diagnosed lung cancer and 379 healthy controls. Genotypes were determined by polymerase chain reaction/restriction fragment length polymorphism method. We found out statistically significant increased risk for lung cancer development between genders. Female carrying XPC Gln/Gln, XPC Lys/Gln+Gln/Gln and XRCC1 Arg/Gln, XRCC1 Arg/Gln+Gln/Gln genotypes had significantly increased risk of lung cancer corresponding to OR = 2.06; p = 0.04, OR = 1.66; p = 0.04 and OR = 1.62; p = 0.04, OR = 1.69; p = 0.02 respectively. In total, significantly increased risk of developing lung cancer was found in the following combinations of genotypes: XPD Lys/Gln+XPC Lys/Lys (OR = 1.62; p = 0.04), XRCC1 Gln/Gln+hOGG1 Ser/Ser (OR = 2.14; p = 0.02). After stratification for genders, the following combinations of genotype were found to be significant in male: XPD Lys/Gln+XPC Lys/Lys (OR = 1.87; p = 0.03), XRCC1 Arg/Gln+XPC Lys/Lys (OR = 4.52; p = 0.0007), XRCC1 Arg/Gln+XPC Lys/Gln (OR = 5.44; p < 0.0001). In female, different combinations of the following genotypes were found to be significant: XRCC1 Arg/Gln+hOGG1 Ser/Ser (OR = 1.98; p = 0.04), XRCC1 Gln/Gln+hOGG1 Ser/Ser (OR = 3.75; p = 0.02), XRCC1 Arg/Gln+XPC Lys/Gln (OR = 2.40; p = 0.04), XRCC1 Arg/Gln+XPC Gln/Gln (OR = 3.03; p = 0.04). We found out decreased cancer risk in genotype combinations between female patients and healthy controls: XPD Lys/Lys+XPC Lys/Gln (OR = 0.45; p = 0.02), XPD Lys/Gln+XPC Lys/Lys (OR = 0.32; p = 0.005), XPD Lys/Gln+XPC Lys/Gln (OR = 0.48; p = 0.02). Our results did not show any difference between pooled smokers and non-smokers in observed gene polymorphisms in the association to the lung cancer risk. However, gender stratification indicated the possible effect of heterozygous constitution of hOGG1 gene (Ser/Cys) on lung cancer risk in female non-smokers (OR = 0.20; p = 0.01) and heterozygous constitution of XPC gene (Lys/Gln) in male smokers (OR = 2.70; p = 0.01).

The influence of XRCC1 genetic variants on lung cancer susceptibility in Chinese Han population

“…Thus, the allele-C and genotype-CC may contribute to play a protection from lung cancer in the studied population (Table 4). These two XRCC1 genetic variants might be linked to other non-synonymous variants, such as Arg194Trp, Arg280His, Arg399Gln, and Glu491Lys, which have been proven to be significantly associated with the susceptibility to lung cancer and influence the function of XRCC1 protein (Hao et al, 2006;Giachino et al, 2007;Lopez-Cima et al, 2007;Sreeja et al, 2008;Chang et al, 2009;Kalikaki et al, 2009;Yin et al, 2009a,b;Butkiewicz et al, 2011;Qian et al, 2011;Chen et al, 2012;Guo et al, 2013a,b;Letkova et al, 2013;Li et al, 2013Li et al, , 2014Wang et al, 2014a,b,c;Zhang et al, 2014a,b). Therefore, the c.482CNT and c.1686CNG genetic variants of XRCC1 gene might play similar functions on the development of lung cancer.…”

“…Previous studies have been indicated that genetic factors play key functions in contributing to lung cancer susceptibility and influencing the prognosis of patients (Viktorsson et al, 2005;Yin et al, 2009a,b). The human X-ray repair cross-complementing group 1 (XRCC1) gene has been regarded as one of the most important candidate genes for influencing the development of lung cancer (Hao et al, 2006;Giachino et al, 2007;Lopez-Cima et al, 2007;Sreeja et al, 2008;Chang et al, 2009;Kalikaki et al, 2009;Wang et al, 2009Wang et al, , 2014aYin et al, 2009a,b;Butkiewicz et al, 2011;Huang et al, 2011Huang et al, , 2013Li et al, 2011Li et al, , 2012Li et al, , 2013Li et al, , 2014Perez-Morales et al, 2011;Qian et al, 2011;Rybarova et al, 2011;Chen et al, 2012;Cui et al, 2012;Dai et al, 2012;Karkucak et al, 2012;Ke et al, 2012;Guo et al, 2013a,b;Letkova et al, 2013;Natukula et al, 2013;Ouyang et al, 2013;Sun et al, 2013;Wu et al, 2013;Zhang et al, 2014a,b). It has been suggested that the XRCC1 proteins play important roles in DNA base excision repair (BER) pathway which affected the etiology of lung cancer.…”

“…XRCC1 is a polygenetic gene, and more than 100 single nucleotide polymorphisms (SNPs) have been detected. Some of the SNPs, (such as arginine (Arg)194 tryptophan (Trp), Arg 280 histidine (His), Arg399 glutanine (Gln), and glutamic (Glu) 491lysine (Lys)) have been reported and identified to play genetic effects on the susceptibility to lung cancer in different populations (Hao et al, 2006;Giachino et al, 2007;Lopez-Cima et al, 2007;Sreeja et al, 2008;Chang et al, 2009;Kalikaki et al, 2009;Yin et al, 2009a,b;Butkiewicz et al, 2011;Qian et al, 2011;Chen et al, 2012;Guo et al, 2013a,b;Letkova et al, 2013;Li et al, 2013Li et al, , 2014Wang et al, 2014a,b,c;Zhang et al, 2014a,b). However, there are no related studies which have investigated the potential genetic effects of XRCC1 c.482CNT and c.1686CNG genetic variants on lung cancer susceptibility.…”

Association of the XRCC1 c.1178G>A Genetic Polymorphism with Lung Cancer Risk in Chinese

“…However, the exact mechanism of lung cancer remains poorly understood. Recently, many studies have investigated the association of lung cancer with genetic polymorphisms of human X-ray repair cross-complementing group 1 (XRCC1) gene in different populations (Hao et al, 2006;Giachino et al, 2007;Lopez-Cima et al, 2007;Sreeja et al, 2008;Chang et al, 2009;Kalikaki et al, 2009;Wang et al, 2009;Butkiewicz et al, 2011;Huang et al, 2011;Li et al, 2011;PerezMorales et al, 2011;Qian et al, 2011;Rybarova et al, 2011;Chen et al, 2012;Cui et al, 2012;Dai et al, 2012;Karkucak et al, 2012;Ke et al, 2012;Li et al, 2012;Huang et al, 2013;Letkova et al, 2013;Natukula et al, 2013;Ouyang et al, 2013;Sun et al, 2013;Wu et al, 2013;. The XRCC1 proteins play important roles in DNA base excision repair (BER) pathway which may be influence the development of lung cancer.…”

“…The XRCC1 genetic polymorphisms may affect the expression and function of XRCC1 proteins, which contributing to the susceptibility of lung cancer and Medicine,Shandong Jining NO.1 People's Hospital,Jining,China *For correspondence: tianfu_12@ sina.com influencing the prognosis of patients (Viktorsson et al, 2005;. Several XRCC1 genetic variants, such as Arg194Trp, Arg 280His and Arg399Gln (Giachino et al, 2007;Lopez-Cima et al, 2007;Sreeja et al, 2008;Kalikaki et al, 2009;Butkiewicz et al, 2011;Qian et al, 2011;Letkova et al, 2013;, have been identified to play potentially influence on the risk of lung cancer in different populations. However, the potential association of XRCC1 c.1178G>A genetic polymorphism with lung cancer risk has not been reported.…”