Prospective Assessment of XPD Lys751Gln and XRCC1 Arg399Gln Single Nucleotide Polymorphisms in Lung Cancer

Abstract

Purpose: XRCC1and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non^small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients. Experimental Design: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy. Results: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P = 0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found. Conclusion: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non^platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

“…10,12,15 On the contrary, some reports in lung cancer didn't find an association between this polymorphism and cisplatin response; [16][17][18] further studies to elucidate the real role of ERCC2 Lys751Gln polymorphism on cisplatin response are warranted. Regarding the other variant in the ERCC2 gene, the ERCC2 Asp312Asn polymorphism, we observed a trend of an increased risk of poor tumor response and reduced EFS, but without reaching the statistical significance.…”

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

“…Therefore, the allele G and genotype GG may be contribute to play a protection from lung cancer in Chinese, and could be a useful molecular biomarker for assessing the risk of lung cancer. The XRCC1 c.1178G>A genetic polymorphism might be linked to other non-synonymous polymorphisms, such as Arg194Trp, Arg280His, Arg399Gln in XRCC1 gene, which have been approved to associate with the risk of lung cancer (Giachino et al, 2007;Lopez-Cima et al, 2007;Sreeja et al, 2008;Chang et al, 2009;Kalikaki et al, 2009;Butkiewicz et al, 2011;Qian et al, 2011;Chen et al, 2012;. These genetic variants might influence the expression and function of XRCC1 proteins in BER pathway, which has been approved to be associated with lung cancer risk (Hao et al, 2006;Giachino et al, 2007;Lopez-Cima et al, 2007;Sreeja et al, 2008;Kalikaki et al, 2009; .…”

“…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.…”

Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array

“…Regarding ERCC2, most of the research has focused on Lys751Gln. Some authors report no association of this SNP with clinical outcome (Giachino et al, 2007;Monzo et al, 2007) or toxicity (Le Morvan et al, 2007), whereas others describe a better anti-tumour response (Park et al, 2001;Ruzzo et al, 2007), longer OS (Stoehlmacher et al, 2004) and increased haematological toxicity (Booton et al, 2006) in wild-type homozygotes. For the other ERCC2 SNP, C499A, no association with OS or response has been reported (Park et al, 2001).…”