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Potential Functional Variants in DNA Repair Genes Are Associated with Efficacy and Toxicity of Radiotherapy in Patients with Non-Small-Cell Lung Cancer

Potential Functional Variants in DNA Repair Genes Are Associated with Efficacy and Toxicity of... Hindawi Journal of Oncology Volume 2020, Article ID 3132786, 7 pages https://doi.org/10.1155/2020/3132786 Research Article Potential Functional Variants in DNA Repair Genes Are Associated with Efficacy and Toxicity of Radiotherapy in Patients with Non-Small-Cell Lung Cancer Zhiguang Yang and Zhaoyu Liu Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110000, China Correspondence should be addressed to Zhaoyu Liu; liuzy1226@126.com Received 6 April 2020; Accepted 9 June 2020; Published 24 June 2020 Academic Editor: Vincenzo Coppola Copyright © 2020 Zhiguang Yang and Zhaoyu Liu. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Lung cancer is one of the leading causes of cancer-related deaths. Radiotherapy, either alone or with chemotherapy, is still the primary treatment for patients with non-small-cell lung cancer (NSCLC). (ere are variations in how patients with NSCLC respond to radiotherapy and how toxic the therapy is. DNA repair gene polymorphisms are related to cancer devel- opment; however, their association with radiotherapy outcomes remains unknown. We hypothesized that gDNA repair gene variation could affect the efficacy and toxicity of radiotherapy in patients with NSCLC. Methods. A total of 486 histologically confirmed patients with NSCLC were recruited from the Shengjing Hospital of China Medical University from July 2015 to September 2019. Eleven potentially functional single nucleotide polymorphisms (SNPs) in four DNA repair genes (XRCC1, XRCC2, XPD, and MSH2) were genotyped in these patients. A multiple factor logistic regression analysis was used to assess the association between these SNPs and the efficacy and toxicity of radiotherapy. Results. (ree SNPs, rs25487 (XRCC1), rs3218556 (XRCC2), and rs13181 (XPD), were all significantly associated with the efficacy of radiotherapy. (e allele frequencies of the rs25487 CC genotype (OR � 0.457, 95% CI � 0.259–0.804, p � 0.006) and the rs3218556 AG or AA genotypes (AG genotype: OR � 0.664, 95% CI � 0.442–0.999, p � 0.049; AA genotype: OR � 0.380, 95% CI � 0.181–0.795, p � 0.008) were both significantly higher in the response group than in the nonresponse group. For rs13181, the radiotherapy efficacy was associated with the heterozygous genotype GT (OR � 1.663, 95% CI � 1.057–2.614,p � 0.027). Statistically significant associations between radiation- induced toxic reactions and rs25487 (XRCC1), rs3218556 (XRCC2), and rs13181 (XPD) were also observed. (e rs13181GT genotype was associated with lower toxic reactions than the TT genotype (OR � 1.680, 95% CI � 1.035–2.728,p � 0.035). Conclusions. (e variants rs25487 (XRCC1), rs3218556 (XRCC2), and rs13181 (XPD) all contribute to the efficacy and toxicity of radiotherapy in patients with NSCLC. Our findings may clarify the predictive value of DNA repair genes for prognosis in patients with NSCLC after radiotherapy. Further investigation of more genes and samples should be performed to confirm our findings. carcinoma (LUSC), accounts for approximately 85% of all 1. Introduction lung cancers [3]. With a better understanding of tumor Lung cancer accounts for a large proportion of cancer pa- biology, there has been a breakthrough in the treatment of tients worldwide and is the leading cause of cancer-related lung cancer. However, radiotherapy, either alone or with deaths [1]. (ere were 9.6 million cancer-related deaths in chemoradiotherapy, is still the primary treatment or palli- 2018, 18.4% of which were caused by lung cancer [2]. In ative care for many patients, especially for locally advanced China, about 28% and 23% of cancer-related death in 2012 NSCLC patients who cannot be surgically resected. (ere is occurred as a result of lung cancer in men and women, often a significant difference in treatment effects and toxic respectively. Non-small-cell lung cancer (NSCLC), includ- reactions in NSCLC patients undergoing standard radio- ing lung adenocarcinoma (LUAD) and lung squamous cell therapy [4, 5]. Genetic variations between individuals or 2 Journal of Oncology Table 1: Clinical characteristics and demographics of the NSCLC Shengjing Hospital of China Medical University from July patients. 2015 to September 2019. (e detailed characteristics of these patients are described in Table 1. (e inclusion criteria were Characteristic NSCLC patients (n � 486) as follows: (1) patients who were diagnosed as having pri- Age (years) 62 (33–84) mary NSCLC and not eligible for surgery; (2) patients who Gender (%) underwent a lung biopsy and had a confirmed histopath- Male 328 (67.5%) ological diagnosis of NSCLC; (3) patients who received a Female 158 (32.5%) standard dose of radiotherapy; (4) patients who had no Smoke history (%) Smokers 244 (50.2%) recurrent disease; (5) patients who had no other malignant Never smokers 242 (49.8%) tumors or history of radiotherapy. All participants or family Histology (%) members signed an informed consent form before blood Squamous cell carcinoma 307 (63.2%) collection and analysis. (is study was approved by the Adenocarcinoma 179 (36.8%) ethics committee of the Shengjing Hospital of China Medical Family history of cancer (%) University. Yes 76 (15.7%) No 410 (84.3%) Chemotherapy (%) 2.2. Radiotherapy Treatment and Evaluation. All patients Yes 383 (78.8%) were treated with three-dimensional conformal radiation No 103 (21.2%) therapy (3D-CRT) or intensity modulated radiation therapy Response (%) (IMRT), with a total radiation dose of 50–70 Gy. Followups Response (CR + PR) 234 (48.1%) were conducted on all patients three months after radio- Nonresponse (SD + PD) 252 (51.9%) therapy, and their response to treatment was assessed using computed omography (CT) according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. tumors are the main reasons for the differences in sensitivity (ere were four categories of response defined: complete to radiotherapy [6]. response (CR), partial response (PR), stable disease (SD), Ionizing radiation leads to cell death mainly by creating and progressive disease (PD) [16]. In the present study, CR double-strand breaks (DSB) [7] or through damage to cell and PR were grouped as “responders,” whereas SD and PD membranes [8]. Studies have shown that DNA repair genes, were grouped as “nonresponders.” Radiation-induced toxic such as ERCC1 [9], XRCC1 [10], and XPA [11], play a key reactions were graded according to the Radiation (erapy role in the different repair processes that are invoked in cells Oncology Group or European Organization for Research following DNA damage. (ere are several DNA repair and Efficacy of Cancer (RTOG/EORTC) guidelines. Patients pathways in the human body, of which the nucleotide ex- with grade 0 and grade 1 reactions were considered to have cision repair (NER), mismatch repair (MMR), and ho- “low-toxic reactions” and those with grades 2–5 reactions, mologous recombination (HR) systems repair the damaged “high-toxic reactions.” DNA after the formation of cross-link chains, whereas the base excision repair (BER) pathway repairs it before the formation of cross-link chains. XRCC1 and XRCC2 are 2.3. Selection of SNPs and Genotyping. Four DNA repair involved in the BER and HR pathways, respectively, and genes, XRCC1, XRCC2, MSH2, and XPD, which had pre- have been associated with the occurrence of cancer [12, 13]. viously been shown to be positively associated with the MutS homolog 2 (MSH2), a key component of the MMR development of cancer, were selected for analysis. SNP pathway, plays an important role in the development of genotypes were downloaded from the 1000 Genomes project neoplastic diseases [14]. (e Xeroderma pigmentosum group (https://www.internationalgenome.org/) and analyzed using D (XPD) gene, another important DNA repair gene, has Haploview 4.2 software (https://www.broadinstitute.org/ been reported to contribute to the risk of human cancer [15]. haploview/haploview). Candidate SNPs which met the fol- Although the relationship between polymorphisms in lowing criteria were included: (1) SNPs that had a minor DNA repair genes and the development of cancer has been allele frequency (MAF)> 0.1 in Han Chinese in Beijing well explored in previous studies, few reports have inves- (CHB); (2) SNPs with a potential function, such as missense tigated the interrelationship between gene polymorphisms variations causing amino acid changes or were present in the and radiosensitivity or radiotherapy toxicity in patients with 5′ or 3′ untranslated regions (UTRs) that could affect NSCLC. To explore the possible association between DNA transcription factor binding site (TFBS) activity; (3) SNPs repair gene variations and radiotherapy sensitivity and as- that have been reported in previous association studies. As a sociated toxicity, we evaluated eleven single nucleotide result of using these selection criteria, a total of 11 potentially polymorphisms (SNPs) in four DNA repair genes (XRCC1, functional SNPs in DNA repair genes were selected. (ese XRCC2, XPD, and MSH2). included 4 XRCC1 SNPs (rs25487 (exon 10), rs25489 (exon 9), rs1799782 (exon (6) and rs3213245 (5′ UTR)), 3 XRCC2 SNPs (rs3218556 (3′ UTR), rs3218544 (3′ UTR), rs3218385 2. Materials and Methods (5′ UTR)), 2 MSH2 SNPs (rs2303424 (exon 16) and 2.1. Study Population. In this study, a total of 486 histo- rs2303425 (5′ UTR)), and 2 XPD SNPs (rs13181 (exon 10) logically confirmed NSCLC patients were recruited from the and rs238419 (3′ UTR)). Journal of Oncology 3 Table 2: Association between candidate SNPs and efficacy of radiotherapy. Gene SNPs Genotype CR + PR SD + PD OR (95% CI) p CC 130 111 Reference Reference CT 81 98 0.706 (0.479–1.041) 0.078 rs25487 TT 23 43 0.457 (0.259–0.804) 0.006 CT + TT 104 141 0.630 (0.440–0.901) 0.011 CC 190 203 Reference Reference CT 42 47 0.955 (0.602–1.514) 0.844 rs25489 TT 2 2 1.068 (0.149–7.661) 0.947 CT + TT 44 49 0.959 (0.610–1.509) 0.858 XRCC1 GG 128 121 Reference Reference AG 84 97 0.819 (0.558–1.201) 0.306 rs1799782 AA 22 34 0.612 (0.339–1.105) 0.101 AG + AA 106 131 0.765 (0.535–1.093) 0.141 AA 182 181 Reference Reference AG 53 66 0.799 (0.527–1.211) 0.289 rs3213245 GG 3 5 0.597 (0.141–2.534) 0.479 AG + GG 56 71 0.784 (0.523–1.178) 0.241 GG 82 78 Reference Reference AG 114 133 0.815 (0.547–1.214) 0.315 rs3218544 AA 38 41 0.882 (0.514–1.512) 0.647 AG + AA 152 174 0.831 (0.569–1.214) 0.338 AA 172 172 Reference Reference AC 53 73 0.726 (0.481–1.096) 0.127 XRCC2 rs3218385 CC 9 7 1.286 (0.468–3.530) 0.625 AC + CC 62 80 0.775 (0.523–1.148) 0.203 GG 166 149 Reference Reference AG 57 77 0.664 (0.442–0.999) 0.049 rs3218556 AA 11 26 0.380 (0.181–0.795) 0.008 AG + AA 68 103 0.593 (0.406–0.865) 0.006 GG 86 102 Reference Reference AG 117 129 1.076 (0.735–1.574) 0.707 rs2303424 AA 31 20 1.599 (0.868–2.945) 0.131 AG + AA 148 149 1.178 (0.817–1.699) 0.380 MSH2 TT 147 166 Reference Reference CT 72 62 1.311 (0.874–1.968) 0.190 rs2303425 CC 15 24 0.706 (0.357–1.396) 0.315 CT + CC 87 86 1.142 (0.788–1.657) 0.483 CC 79 95 Reference Reference CT 101 110 1.104 (0.738–1.651) 0.629 rs238419 TT 54 47 1.382 (0.845–2.259) 0.197 CT + TT 155 157 1.187 (0.818–1.722) 0.366 XPD TT 176 209 Reference Reference GT 56 40 1.663 (1.057–2.614) 0.027 rs13181 GG 2 3 0.792 (0.131–4.791) 0.799 GT + GG 58 43 1.602 (1.029–2.493) 0.036 (e p values in bold represent a statistically significant association. All data are adjusted for age, gender, smoking history, cancer histology, family history, and treatment with chemotherapy. ° ° Genomic DNA from all patients was extracted using a cycles of 95 C for 15 sec, 60 C for 1 min. (ree negative TIANamp Genomic DNA Kit (Tiangen Biotech, Beijing, controls (no DNA) and three positive controls in each 96- China). Genotyping was performed using the TaqMan well plate were used to ensure the accuracy of the PCR methodology and an Applied Biosystems 7500 FAST Real- amplification. In addition, 10% of randomly repeated Time PCR System (Applied Biosystems, Foster City, CA, samples were used for quality control. USA) according to the manufacturer’s instructions. (e predesigned SNP-genotyping assay mixture, containing the PCR primers and probes, were supplied by Applied Bio- 2.4. Statistical Analysis. Statistical analyses were performed using SPSS 22.0 software (SPSS, Chicago, IL, USA). (e systems. (e PCR amplification mix was prepared as follows: 25 μL of master mix (Applied Biosystems), 10 μL of DNA, Hardy-Weinberg equilibrium was used to assess that all SNPs met the group representation. A multiple factor lo- and 15 μL of ddH O. Amplification was performed under ° ° the following conditions: 50 C for 2 min, 95 C for 10 min, 40 gistic regression was applied to assess the association 4 Journal of Oncology compared with the TT genotype (OR � 1.680, 95% between SNPs and efficacy of radiotherapy as well as ra- diation-induced toxicity reaction after adjusting for age, CI � 1.035–2.728, p � 0.035). gender, smoking history, cancer histology, family history, and chemotherapy. A p< 0.05 was considered statistically 4. Discussion significant. NSCLC is the leading cause of cancer-related death. Ra- diotherapy is an important treatment for NSCLC patients, 3. Results especially for advanced NSCLC patients. However, there are 3.1. Characteristics of Patients and Clinical Outcomes. (e significant differences in the efficacy of radiotherapy as well clinical characteristics and demographics of the 486 NSCLC as in the incidence rate for radiation-induced toxic reactions. patients are described in Table 1. (e proportion of male Identification of the key determinants that affect efficacy and patients (67.5%) was greater than double the proportion of toxicity is of paramount importance for the efficacy of ra- female patients (32.5%). (e median age of all patients was diotherapy in patients with NSCLC. Although numerous 62 (ranging from 33 to 84). About half of the patients had a studies have reported that genetic polymorphisms in DNA history of smoking. (ere were 307 (63.2%) cases of repair genes are related to the development of cancer, their squamous cell carcinoma and 179 (36.8%) cases of adeno- association with the outcomes of radiotherapy remains carcinoma. Seventy-six patients (15.7%) had a family history unknown. In the present study, we demonstrated that of cancer and 383 (78.8%) had been treated with chemo- rs25487 (XRCC1), rs3218556 (XRCC2), and rs13181 (XPD) therapy. (e response rate to radiotherapy was 48.1%. were associated with the efficacy and toxicity of radiotherapy in patients with NSCLC. (e potential functional variations of the four DNA 3.2. Associations between Candidate SNPs and Efficacy of repair genes were listed in Supplementary Table 1. (e Radiotherapy. (e associations between candidate SNPs variations of rs25487 (c.1196A> G, p. Gln399Arg), rs25489 and the response to radiotherapy in NSCLS patients are (c.839G> A, p. Arg280His), rs1799782 (c.580C> T, p. shown in Table 2. All the candidate SNPs reached equilib- Arg194Trp) of XRCC1 gene, rs2303424 (c.2744A> G, p. rium according to the Hardy-Weinberg equilibrium test Gln915Arg) of MSH2 gene, and rs13181 (c.2251A> C, p. (p> 0.05, data not shown). (e SNPs rs25487 (XRCC1), Lys751Gln) of XPD gene cause amino acid changes and then rs3218556 (XRCC2), and rs13181 (XPD) all showed a sig- affect the biological function of the protein. Also, other nificant association with the efficacy of radiotherapy. (e variations located in the 5′ or 3′ UTRs may affect the allele frequency of rs25487 CC genotype (OR � 0.457, 95% transcription factor binding site (TFBS) activity and then CI � 0.259–0.804,p � 0.006) and the rs3218556 AG or AA influence the DNA repair gene expression. All the variants genotypes (AG genotype: OR � 0.664, 95% may impact the clinical outcome of radiotherapy through CI � 0.442–0.999,p � 0.049; AA genotype: OR � 0.380, 95% these two ways. CI � 0.181–0.795, p � 0.008) were significantly higher in the Many genetic variants that are involved in DNA damage response group than in the nonresponse group. For rs25487, repair and the regulation of oxidative stress are associated although the response rate between the CT and CC geno- with radiotherapy outcomes [17]. XRCC1, an important types was not statistically significant (p � 0.078), a higher component of BER, has been reported to be associated with response rate was also observed when comparing the an increased risk of NSCLC in nonsmoking female patients CT + CC genotype with the CC genotype, using a dominant with a history of exposure to cooking oil mist [10]. Genetic model. For rs13181, a better radiotherapy efficacy was as- polymorphisms in XRCC1-194 and XRCC1-399 are also sociated with the heterozygotic genotype GT (OR � 1.663, related to the risk of NSCLC [18]. Wang et al. [19] have 95% CI � 1.057–2.614, p � 0.027). (ere were no significant reported that the presence of XRCC1 rs25489 had a sig- associations between the other SNPs and the efficacy of nificant impact on primary tumor efficacy at the end of radiotherapy. radiotherapy and may act as a biomarker for the curative effect of radiotherapy. Zhai et al. [20] found that patients 3.3. Associations between Candidate SNPs and Radiation- with nasopharyngeal carcinoma (NPC) carrying the XRCC1 codon 399 Gln/Gln genotype had a higher rate of tumor Induced Toxic Reactions. (e associations between candi- date SNPs and radiation-induced toxic reactions are shown regression after radiotherapy. Another study showed that, in in Table 3. A statistically significant association between 114 patients with NPC, the XRCC1 rs25487 GA genotype radiation-induced toxic reactions and rs25487 (XRCC1), was related with grade 3 dermatitis and grade 3 mucositis. In rs3218556 (XRCC2), and rs13181 (XPD) was observed. For this study, a significant association was also observed be- rs25487, the genotypes CT, TT, and CT + TT were associated tween the rs25489 CC genotype and a higher response rate to with a severe toxic reaction compared to the CC genotype radiotherapy as well as lower toxic reaction. Although three (all, p< 0.05). For rs3218556, the ORs for cases with the AG, other SNPs (rs25489, rs1799782, and rs3213245) in XRCC1 AA, and AG + AA genotypes compared with homozygous were also genotyped, no significant associations were ob- CC genotype were 0.605 (95% CI � 0.396–0.924, p � 0.019), served. Due to the fact that XRCC1 rs25487 is clearly im- 0.279 (95% CI � 0.116–0.675, p � 0.003), and 0.540 (95% portant in radiation sensitivity and the resultant toxic reactions, it could be considered as a biomarker that can be CI � 0.362–0.805, p � 0.002), respectively. (e rs13181GT genotype was associated with lower toxic reactions used to predict the clinical outcomes of radiotherapy. Journal of Oncology 5 Table 3: Association between candidate SNPs and radiation-induced toxic reactions. Gene SNPs Genotype Low toxic reactions High toxic reactions OR (95% CI) p CC 188 74 Reference Reference CT 114 69 0.650 (0.435–0.972) 0.035 rs25487 TT 23 18 0.503 (0.257–0.986) 0.043 CT + TT 137 87 0.620 (0.424–0.907) 0.013 CC 257 122 Reference Reference CT 65 38 0.812 (0.515–1.279) 0.369 rs25489 TT 3 1 0.424 (0.147–13.83) 0.759 CT + TT 68 39 0.828 (0.528–1.297) 0.409 XRCC1 GG 175 91 Reference Reference AG 117 58 1.049 (0.700–1.571) 0.817 rs1799782 AA 33 12 1.430 (0.705–2.902) 0.320 AG + AA 150 70 1.114 (0.762–1.630) 0.577 AA 248 117 Reference Reference AG 74 43 0.812 (0.525–1.255) 0.348 rs3213245 GG 3 1 1.415 (0.146–13.75) 0.764 AG + GG 77 44 0.826 (0.537–1.270) 0.383 GG 117 49 Reference Reference AG 162 83 0.817 (0.534–1.251) 0.353 rs3218544 AA 46 28 0.688 (0.387–1.224) 0.202 AG + AA 208 111 0.785 (0.523–1.177) 0.241 AA 235 109 Reference Reference AC 78 47 0.770 (0.502–1.180) 0.229 XRCC2 rs3218385 CC 12 5 1.113 (0.383–3.238) 0.844 AC + CC 90 52 0.803 (0.533–1.210) 0.293 GG 238 96 Reference Reference AG 78 52 0.605 (0.396–0.924) 0.019 rs3218556 AA 9 13 0.279 (0.116–0.675) 0.003 AG + AA 87 65 0.540 (0.362–0.805) 0.002 GG 123 52 Reference Reference AG 156 82 0.804 (0.528–1.224) 0.309 rs2303424 AA 46 27 0.720 (0.405–1.280) 0.263 AG + AA 202 109 0.783 (0.526–1.168) 0.230 MSH2 TT 204 106 Reference Reference CT 104 45 1.201 (0.788–1.830) 0.394 rs2303425 CC 17 10 0.883 (0.391–1.997) 0.765 CT + CC 121 55 1.143 (0.769–1.698) 0.508 CC 102 43 Reference Reference CT 149 77 0.816 (0.520–1.280) 0.375 rs238419 TT 74 41 0.761 (0.451–1.283) 0.304 CT + TT 223 118 0.797 (0.523–1.213) 0.289 XPD TT 235 130 Reference Reference GT 82 27 1.680 (1.035–2.728) 0.035 rs13181 GG 8 4 1.106 (0.327–3.745) 0.871 GT + GG 90 31 1.624 (1.025–2.547) 0.038 (e p values in bold indicate a statistically significant association. All data are adjusted for age, gender, smoking history, cancer histology, family history, and treatment with chemotherapy. (ree SNPs (rs3218556, rs3218544, and rs3218385) in XRCC2 R188H SNPs was independent prognostic factor for XRCC2, which is involved in the HR pathway, were also overall survival. Qin et al. [22] also found that XRCC2- evaluated for a possible association with the efficacy and deficient cancer cells were more sensitive to irradiation in toxicity of radiotherapy in patients with NSCLC. Of these, vitro and speculated that the inhibition of XRCC2 expression only rs3218385 showed a significant association with both or activity represents a potential therapeutic strategy for the efficacy and toxicity of radiotherapy. Popanda et al. [7] improving preoperative radiotherapy responses in patients suggested that there was no relationship between the risk of with locally advanced rectal cancer. (ese results strongly acute skin toxicity and XRCC2 variations in patients with suggest that XRCC2 plays an important role not only in the breast cancer receiving radiotherapy, which is inconsistent development of the cancer but also in radiotherapy with our findings. Nevertheless, Yin et al. [21] genotyped six outcomes. MSH2 is an important MMR gene and several studies potentially functional SNPs in 228 patients with NSCLC who had been treated with definitive radiotherapy and found that have suggested that variations in MSH2 are associated with 6 Journal of Oncology sensitivity to radiotherapy and disease progression in rectal Supplementary Materials cancer patients [23, 24]. However, the present study found Supplementary Table 1: genomic function of the ten SNPs in that there was no association between two SNPs in this gene XRCC1, XRCC2, MSH2, and XPD genes. (Supplementary (rs2303424 and rs2303425) and the efficacy of radiotherapy. Materials) Xie et al. 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Dong, “Expression of ERCC1, MSH2 and PARP1 in non- http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Oncology Hindawi Publishing Corporation

Potential Functional Variants in DNA Repair Genes Are Associated with Efficacy and Toxicity of Radiotherapy in Patients with Non-Small-Cell Lung Cancer

Journal of Oncology , Volume 2020 – Jun 24, 2020

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Copyright © 2020 Zhiguang Yang and Zhaoyu Liu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Oncology Volume 2020, Article ID 3132786, 7 pages https://doi.org/10.1155/2020/3132786 Research Article Potential Functional Variants in DNA Repair Genes Are Associated with Efficacy and Toxicity of Radiotherapy in Patients with Non-Small-Cell Lung Cancer Zhiguang Yang and Zhaoyu Liu Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110000, China Correspondence should be addressed to Zhaoyu Liu; liuzy1226@126.com Received 6 April 2020; Accepted 9 June 2020; Published 24 June 2020 Academic Editor: Vincenzo Coppola Copyright © 2020 Zhiguang Yang and Zhaoyu Liu. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Lung cancer is one of the leading causes of cancer-related deaths. Radiotherapy, either alone or with chemotherapy, is still the primary treatment for patients with non-small-cell lung cancer (NSCLC). (ere are variations in how patients with NSCLC respond to radiotherapy and how toxic the therapy is. DNA repair gene polymorphisms are related to cancer devel- opment; however, their association with radiotherapy outcomes remains unknown. We hypothesized that gDNA repair gene variation could affect the efficacy and toxicity of radiotherapy in patients with NSCLC. Methods. A total of 486 histologically confirmed patients with NSCLC were recruited from the Shengjing Hospital of China Medical University from July 2015 to September 2019. Eleven potentially functional single nucleotide polymorphisms (SNPs) in four DNA repair genes (XRCC1, XRCC2, XPD, and MSH2) were genotyped in these patients. A multiple factor logistic regression analysis was used to assess the association between these SNPs and the efficacy and toxicity of radiotherapy. Results. (ree SNPs, rs25487 (XRCC1), rs3218556 (XRCC2), and rs13181 (XPD), were all significantly associated with the efficacy of radiotherapy. (e allele frequencies of the rs25487 CC genotype (OR � 0.457, 95% CI � 0.259–0.804, p � 0.006) and the rs3218556 AG or AA genotypes (AG genotype: OR � 0.664, 95% CI � 0.442–0.999, p � 0.049; AA genotype: OR � 0.380, 95% CI � 0.181–0.795, p � 0.008) were both significantly higher in the response group than in the nonresponse group. For rs13181, the radiotherapy efficacy was associated with the heterozygous genotype GT (OR � 1.663, 95% CI � 1.057–2.614,p � 0.027). Statistically significant associations between radiation- induced toxic reactions and rs25487 (XRCC1), rs3218556 (XRCC2), and rs13181 (XPD) were also observed. (e rs13181GT genotype was associated with lower toxic reactions than the TT genotype (OR � 1.680, 95% CI � 1.035–2.728,p � 0.035). Conclusions. (e variants rs25487 (XRCC1), rs3218556 (XRCC2), and rs13181 (XPD) all contribute to the efficacy and toxicity of radiotherapy in patients with NSCLC. Our findings may clarify the predictive value of DNA repair genes for prognosis in patients with NSCLC after radiotherapy. Further investigation of more genes and samples should be performed to confirm our findings. carcinoma (LUSC), accounts for approximately 85% of all 1. Introduction lung cancers [3]. With a better understanding of tumor Lung cancer accounts for a large proportion of cancer pa- biology, there has been a breakthrough in the treatment of tients worldwide and is the leading cause of cancer-related lung cancer. However, radiotherapy, either alone or with deaths [1]. (ere were 9.6 million cancer-related deaths in chemoradiotherapy, is still the primary treatment or palli- 2018, 18.4% of which were caused by lung cancer [2]. In ative care for many patients, especially for locally advanced China, about 28% and 23% of cancer-related death in 2012 NSCLC patients who cannot be surgically resected. (ere is occurred as a result of lung cancer in men and women, often a significant difference in treatment effects and toxic respectively. Non-small-cell lung cancer (NSCLC), includ- reactions in NSCLC patients undergoing standard radio- ing lung adenocarcinoma (LUAD) and lung squamous cell therapy [4, 5]. Genetic variations between individuals or 2 Journal of Oncology Table 1: Clinical characteristics and demographics of the NSCLC Shengjing Hospital of China Medical University from July patients. 2015 to September 2019. (e detailed characteristics of these patients are described in Table 1. (e inclusion criteria were Characteristic NSCLC patients (n � 486) as follows: (1) patients who were diagnosed as having pri- Age (years) 62 (33–84) mary NSCLC and not eligible for surgery; (2) patients who Gender (%) underwent a lung biopsy and had a confirmed histopath- Male 328 (67.5%) ological diagnosis of NSCLC; (3) patients who received a Female 158 (32.5%) standard dose of radiotherapy; (4) patients who had no Smoke history (%) Smokers 244 (50.2%) recurrent disease; (5) patients who had no other malignant Never smokers 242 (49.8%) tumors or history of radiotherapy. All participants or family Histology (%) members signed an informed consent form before blood Squamous cell carcinoma 307 (63.2%) collection and analysis. (is study was approved by the Adenocarcinoma 179 (36.8%) ethics committee of the Shengjing Hospital of China Medical Family history of cancer (%) University. Yes 76 (15.7%) No 410 (84.3%) Chemotherapy (%) 2.2. Radiotherapy Treatment and Evaluation. All patients Yes 383 (78.8%) were treated with three-dimensional conformal radiation No 103 (21.2%) therapy (3D-CRT) or intensity modulated radiation therapy Response (%) (IMRT), with a total radiation dose of 50–70 Gy. Followups Response (CR + PR) 234 (48.1%) were conducted on all patients three months after radio- Nonresponse (SD + PD) 252 (51.9%) therapy, and their response to treatment was assessed using computed omography (CT) according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. tumors are the main reasons for the differences in sensitivity (ere were four categories of response defined: complete to radiotherapy [6]. response (CR), partial response (PR), stable disease (SD), Ionizing radiation leads to cell death mainly by creating and progressive disease (PD) [16]. In the present study, CR double-strand breaks (DSB) [7] or through damage to cell and PR were grouped as “responders,” whereas SD and PD membranes [8]. Studies have shown that DNA repair genes, were grouped as “nonresponders.” Radiation-induced toxic such as ERCC1 [9], XRCC1 [10], and XPA [11], play a key reactions were graded according to the Radiation (erapy role in the different repair processes that are invoked in cells Oncology Group or European Organization for Research following DNA damage. (ere are several DNA repair and Efficacy of Cancer (RTOG/EORTC) guidelines. Patients pathways in the human body, of which the nucleotide ex- with grade 0 and grade 1 reactions were considered to have cision repair (NER), mismatch repair (MMR), and ho- “low-toxic reactions” and those with grades 2–5 reactions, mologous recombination (HR) systems repair the damaged “high-toxic reactions.” DNA after the formation of cross-link chains, whereas the base excision repair (BER) pathway repairs it before the formation of cross-link chains. XRCC1 and XRCC2 are 2.3. Selection of SNPs and Genotyping. Four DNA repair involved in the BER and HR pathways, respectively, and genes, XRCC1, XRCC2, MSH2, and XPD, which had pre- have been associated with the occurrence of cancer [12, 13]. viously been shown to be positively associated with the MutS homolog 2 (MSH2), a key component of the MMR development of cancer, were selected for analysis. SNP pathway, plays an important role in the development of genotypes were downloaded from the 1000 Genomes project neoplastic diseases [14]. (e Xeroderma pigmentosum group (https://www.internationalgenome.org/) and analyzed using D (XPD) gene, another important DNA repair gene, has Haploview 4.2 software (https://www.broadinstitute.org/ been reported to contribute to the risk of human cancer [15]. haploview/haploview). Candidate SNPs which met the fol- Although the relationship between polymorphisms in lowing criteria were included: (1) SNPs that had a minor DNA repair genes and the development of cancer has been allele frequency (MAF)> 0.1 in Han Chinese in Beijing well explored in previous studies, few reports have inves- (CHB); (2) SNPs with a potential function, such as missense tigated the interrelationship between gene polymorphisms variations causing amino acid changes or were present in the and radiosensitivity or radiotherapy toxicity in patients with 5′ or 3′ untranslated regions (UTRs) that could affect NSCLC. To explore the possible association between DNA transcription factor binding site (TFBS) activity; (3) SNPs repair gene variations and radiotherapy sensitivity and as- that have been reported in previous association studies. As a sociated toxicity, we evaluated eleven single nucleotide result of using these selection criteria, a total of 11 potentially polymorphisms (SNPs) in four DNA repair genes (XRCC1, functional SNPs in DNA repair genes were selected. (ese XRCC2, XPD, and MSH2). included 4 XRCC1 SNPs (rs25487 (exon 10), rs25489 (exon 9), rs1799782 (exon (6) and rs3213245 (5′ UTR)), 3 XRCC2 SNPs (rs3218556 (3′ UTR), rs3218544 (3′ UTR), rs3218385 2. Materials and Methods (5′ UTR)), 2 MSH2 SNPs (rs2303424 (exon 16) and 2.1. Study Population. In this study, a total of 486 histo- rs2303425 (5′ UTR)), and 2 XPD SNPs (rs13181 (exon 10) logically confirmed NSCLC patients were recruited from the and rs238419 (3′ UTR)). Journal of Oncology 3 Table 2: Association between candidate SNPs and efficacy of radiotherapy. Gene SNPs Genotype CR + PR SD + PD OR (95% CI) p CC 130 111 Reference Reference CT 81 98 0.706 (0.479–1.041) 0.078 rs25487 TT 23 43 0.457 (0.259–0.804) 0.006 CT + TT 104 141 0.630 (0.440–0.901) 0.011 CC 190 203 Reference Reference CT 42 47 0.955 (0.602–1.514) 0.844 rs25489 TT 2 2 1.068 (0.149–7.661) 0.947 CT + TT 44 49 0.959 (0.610–1.509) 0.858 XRCC1 GG 128 121 Reference Reference AG 84 97 0.819 (0.558–1.201) 0.306 rs1799782 AA 22 34 0.612 (0.339–1.105) 0.101 AG + AA 106 131 0.765 (0.535–1.093) 0.141 AA 182 181 Reference Reference AG 53 66 0.799 (0.527–1.211) 0.289 rs3213245 GG 3 5 0.597 (0.141–2.534) 0.479 AG + GG 56 71 0.784 (0.523–1.178) 0.241 GG 82 78 Reference Reference AG 114 133 0.815 (0.547–1.214) 0.315 rs3218544 AA 38 41 0.882 (0.514–1.512) 0.647 AG + AA 152 174 0.831 (0.569–1.214) 0.338 AA 172 172 Reference Reference AC 53 73 0.726 (0.481–1.096) 0.127 XRCC2 rs3218385 CC 9 7 1.286 (0.468–3.530) 0.625 AC + CC 62 80 0.775 (0.523–1.148) 0.203 GG 166 149 Reference Reference AG 57 77 0.664 (0.442–0.999) 0.049 rs3218556 AA 11 26 0.380 (0.181–0.795) 0.008 AG + AA 68 103 0.593 (0.406–0.865) 0.006 GG 86 102 Reference Reference AG 117 129 1.076 (0.735–1.574) 0.707 rs2303424 AA 31 20 1.599 (0.868–2.945) 0.131 AG + AA 148 149 1.178 (0.817–1.699) 0.380 MSH2 TT 147 166 Reference Reference CT 72 62 1.311 (0.874–1.968) 0.190 rs2303425 CC 15 24 0.706 (0.357–1.396) 0.315 CT + CC 87 86 1.142 (0.788–1.657) 0.483 CC 79 95 Reference Reference CT 101 110 1.104 (0.738–1.651) 0.629 rs238419 TT 54 47 1.382 (0.845–2.259) 0.197 CT + TT 155 157 1.187 (0.818–1.722) 0.366 XPD TT 176 209 Reference Reference GT 56 40 1.663 (1.057–2.614) 0.027 rs13181 GG 2 3 0.792 (0.131–4.791) 0.799 GT + GG 58 43 1.602 (1.029–2.493) 0.036 (e p values in bold represent a statistically significant association. All data are adjusted for age, gender, smoking history, cancer histology, family history, and treatment with chemotherapy. ° ° Genomic DNA from all patients was extracted using a cycles of 95 C for 15 sec, 60 C for 1 min. (ree negative TIANamp Genomic DNA Kit (Tiangen Biotech, Beijing, controls (no DNA) and three positive controls in each 96- China). Genotyping was performed using the TaqMan well plate were used to ensure the accuracy of the PCR methodology and an Applied Biosystems 7500 FAST Real- amplification. In addition, 10% of randomly repeated Time PCR System (Applied Biosystems, Foster City, CA, samples were used for quality control. USA) according to the manufacturer’s instructions. (e predesigned SNP-genotyping assay mixture, containing the PCR primers and probes, were supplied by Applied Bio- 2.4. Statistical Analysis. Statistical analyses were performed using SPSS 22.0 software (SPSS, Chicago, IL, USA). (e systems. (e PCR amplification mix was prepared as follows: 25 μL of master mix (Applied Biosystems), 10 μL of DNA, Hardy-Weinberg equilibrium was used to assess that all SNPs met the group representation. A multiple factor lo- and 15 μL of ddH O. Amplification was performed under ° ° the following conditions: 50 C for 2 min, 95 C for 10 min, 40 gistic regression was applied to assess the association 4 Journal of Oncology compared with the TT genotype (OR � 1.680, 95% between SNPs and efficacy of radiotherapy as well as ra- diation-induced toxicity reaction after adjusting for age, CI � 1.035–2.728, p � 0.035). gender, smoking history, cancer histology, family history, and chemotherapy. A p< 0.05 was considered statistically 4. Discussion significant. NSCLC is the leading cause of cancer-related death. Ra- diotherapy is an important treatment for NSCLC patients, 3. Results especially for advanced NSCLC patients. However, there are 3.1. Characteristics of Patients and Clinical Outcomes. (e significant differences in the efficacy of radiotherapy as well clinical characteristics and demographics of the 486 NSCLC as in the incidence rate for radiation-induced toxic reactions. patients are described in Table 1. (e proportion of male Identification of the key determinants that affect efficacy and patients (67.5%) was greater than double the proportion of toxicity is of paramount importance for the efficacy of ra- female patients (32.5%). (e median age of all patients was diotherapy in patients with NSCLC. Although numerous 62 (ranging from 33 to 84). About half of the patients had a studies have reported that genetic polymorphisms in DNA history of smoking. (ere were 307 (63.2%) cases of repair genes are related to the development of cancer, their squamous cell carcinoma and 179 (36.8%) cases of adeno- association with the outcomes of radiotherapy remains carcinoma. Seventy-six patients (15.7%) had a family history unknown. In the present study, we demonstrated that of cancer and 383 (78.8%) had been treated with chemo- rs25487 (XRCC1), rs3218556 (XRCC2), and rs13181 (XPD) therapy. (e response rate to radiotherapy was 48.1%. were associated with the efficacy and toxicity of radiotherapy in patients with NSCLC. (e potential functional variations of the four DNA 3.2. Associations between Candidate SNPs and Efficacy of repair genes were listed in Supplementary Table 1. (e Radiotherapy. (e associations between candidate SNPs variations of rs25487 (c.1196A> G, p. Gln399Arg), rs25489 and the response to radiotherapy in NSCLS patients are (c.839G> A, p. Arg280His), rs1799782 (c.580C> T, p. shown in Table 2. All the candidate SNPs reached equilib- Arg194Trp) of XRCC1 gene, rs2303424 (c.2744A> G, p. rium according to the Hardy-Weinberg equilibrium test Gln915Arg) of MSH2 gene, and rs13181 (c.2251A> C, p. (p> 0.05, data not shown). (e SNPs rs25487 (XRCC1), Lys751Gln) of XPD gene cause amino acid changes and then rs3218556 (XRCC2), and rs13181 (XPD) all showed a sig- affect the biological function of the protein. Also, other nificant association with the efficacy of radiotherapy. (e variations located in the 5′ or 3′ UTRs may affect the allele frequency of rs25487 CC genotype (OR � 0.457, 95% transcription factor binding site (TFBS) activity and then CI � 0.259–0.804,p � 0.006) and the rs3218556 AG or AA influence the DNA repair gene expression. All the variants genotypes (AG genotype: OR � 0.664, 95% may impact the clinical outcome of radiotherapy through CI � 0.442–0.999,p � 0.049; AA genotype: OR � 0.380, 95% these two ways. CI � 0.181–0.795, p � 0.008) were significantly higher in the Many genetic variants that are involved in DNA damage response group than in the nonresponse group. For rs25487, repair and the regulation of oxidative stress are associated although the response rate between the CT and CC geno- with radiotherapy outcomes [17]. XRCC1, an important types was not statistically significant (p � 0.078), a higher component of BER, has been reported to be associated with response rate was also observed when comparing the an increased risk of NSCLC in nonsmoking female patients CT + CC genotype with the CC genotype, using a dominant with a history of exposure to cooking oil mist [10]. Genetic model. For rs13181, a better radiotherapy efficacy was as- polymorphisms in XRCC1-194 and XRCC1-399 are also sociated with the heterozygotic genotype GT (OR � 1.663, related to the risk of NSCLC [18]. Wang et al. [19] have 95% CI � 1.057–2.614, p � 0.027). (ere were no significant reported that the presence of XRCC1 rs25489 had a sig- associations between the other SNPs and the efficacy of nificant impact on primary tumor efficacy at the end of radiotherapy. radiotherapy and may act as a biomarker for the curative effect of radiotherapy. Zhai et al. [20] found that patients 3.3. Associations between Candidate SNPs and Radiation- with nasopharyngeal carcinoma (NPC) carrying the XRCC1 codon 399 Gln/Gln genotype had a higher rate of tumor Induced Toxic Reactions. (e associations between candi- date SNPs and radiation-induced toxic reactions are shown regression after radiotherapy. Another study showed that, in in Table 3. A statistically significant association between 114 patients with NPC, the XRCC1 rs25487 GA genotype radiation-induced toxic reactions and rs25487 (XRCC1), was related with grade 3 dermatitis and grade 3 mucositis. In rs3218556 (XRCC2), and rs13181 (XPD) was observed. For this study, a significant association was also observed be- rs25487, the genotypes CT, TT, and CT + TT were associated tween the rs25489 CC genotype and a higher response rate to with a severe toxic reaction compared to the CC genotype radiotherapy as well as lower toxic reaction. Although three (all, p< 0.05). For rs3218556, the ORs for cases with the AG, other SNPs (rs25489, rs1799782, and rs3213245) in XRCC1 AA, and AG + AA genotypes compared with homozygous were also genotyped, no significant associations were ob- CC genotype were 0.605 (95% CI � 0.396–0.924, p � 0.019), served. Due to the fact that XRCC1 rs25487 is clearly im- 0.279 (95% CI � 0.116–0.675, p � 0.003), and 0.540 (95% portant in radiation sensitivity and the resultant toxic reactions, it could be considered as a biomarker that can be CI � 0.362–0.805, p � 0.002), respectively. (e rs13181GT genotype was associated with lower toxic reactions used to predict the clinical outcomes of radiotherapy. Journal of Oncology 5 Table 3: Association between candidate SNPs and radiation-induced toxic reactions. Gene SNPs Genotype Low toxic reactions High toxic reactions OR (95% CI) p CC 188 74 Reference Reference CT 114 69 0.650 (0.435–0.972) 0.035 rs25487 TT 23 18 0.503 (0.257–0.986) 0.043 CT + TT 137 87 0.620 (0.424–0.907) 0.013 CC 257 122 Reference Reference CT 65 38 0.812 (0.515–1.279) 0.369 rs25489 TT 3 1 0.424 (0.147–13.83) 0.759 CT + TT 68 39 0.828 (0.528–1.297) 0.409 XRCC1 GG 175 91 Reference Reference AG 117 58 1.049 (0.700–1.571) 0.817 rs1799782 AA 33 12 1.430 (0.705–2.902) 0.320 AG + AA 150 70 1.114 (0.762–1.630) 0.577 AA 248 117 Reference Reference AG 74 43 0.812 (0.525–1.255) 0.348 rs3213245 GG 3 1 1.415 (0.146–13.75) 0.764 AG + GG 77 44 0.826 (0.537–1.270) 0.383 GG 117 49 Reference Reference AG 162 83 0.817 (0.534–1.251) 0.353 rs3218544 AA 46 28 0.688 (0.387–1.224) 0.202 AG + AA 208 111 0.785 (0.523–1.177) 0.241 AA 235 109 Reference Reference AC 78 47 0.770 (0.502–1.180) 0.229 XRCC2 rs3218385 CC 12 5 1.113 (0.383–3.238) 0.844 AC + CC 90 52 0.803 (0.533–1.210) 0.293 GG 238 96 Reference Reference AG 78 52 0.605 (0.396–0.924) 0.019 rs3218556 AA 9 13 0.279 (0.116–0.675) 0.003 AG + AA 87 65 0.540 (0.362–0.805) 0.002 GG 123 52 Reference Reference AG 156 82 0.804 (0.528–1.224) 0.309 rs2303424 AA 46 27 0.720 (0.405–1.280) 0.263 AG + AA 202 109 0.783 (0.526–1.168) 0.230 MSH2 TT 204 106 Reference Reference CT 104 45 1.201 (0.788–1.830) 0.394 rs2303425 CC 17 10 0.883 (0.391–1.997) 0.765 CT + CC 121 55 1.143 (0.769–1.698) 0.508 CC 102 43 Reference Reference CT 149 77 0.816 (0.520–1.280) 0.375 rs238419 TT 74 41 0.761 (0.451–1.283) 0.304 CT + TT 223 118 0.797 (0.523–1.213) 0.289 XPD TT 235 130 Reference Reference GT 82 27 1.680 (1.035–2.728) 0.035 rs13181 GG 8 4 1.106 (0.327–3.745) 0.871 GT + GG 90 31 1.624 (1.025–2.547) 0.038 (e p values in bold indicate a statistically significant association. All data are adjusted for age, gender, smoking history, cancer histology, family history, and treatment with chemotherapy. (ree SNPs (rs3218556, rs3218544, and rs3218385) in XRCC2 R188H SNPs was independent prognostic factor for XRCC2, which is involved in the HR pathway, were also overall survival. Qin et al. [22] also found that XRCC2- evaluated for a possible association with the efficacy and deficient cancer cells were more sensitive to irradiation in toxicity of radiotherapy in patients with NSCLC. Of these, vitro and speculated that the inhibition of XRCC2 expression only rs3218385 showed a significant association with both or activity represents a potential therapeutic strategy for the efficacy and toxicity of radiotherapy. Popanda et al. [7] improving preoperative radiotherapy responses in patients suggested that there was no relationship between the risk of with locally advanced rectal cancer. (ese results strongly acute skin toxicity and XRCC2 variations in patients with suggest that XRCC2 plays an important role not only in the breast cancer receiving radiotherapy, which is inconsistent development of the cancer but also in radiotherapy with our findings. Nevertheless, Yin et al. [21] genotyped six outcomes. MSH2 is an important MMR gene and several studies potentially functional SNPs in 228 patients with NSCLC who had been treated with definitive radiotherapy and found that have suggested that variations in MSH2 are associated with 6 Journal of Oncology sensitivity to radiotherapy and disease progression in rectal Supplementary Materials cancer patients [23, 24]. However, the present study found Supplementary Table 1: genomic function of the ten SNPs in that there was no association between two SNPs in this gene XRCC1, XRCC2, MSH2, and XPD genes. (Supplementary (rs2303424 and rs2303425) and the efficacy of radiotherapy. Materials) Xie et al. 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