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 Table of Contents  
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 72-78

Dual-specificity phosphatase 6 genetic variants associated with risk of lung squamous cell carcinoma in Han Chinese

1 Department of Radiotherapy Oncology, The Fourth Hospital of China Medical University; Liaoning Cancer Hospital and Institute, Shenyang 110042, China
2 Department of Radiotherapy Oncology, Liaoning Cancer Hospital and Institute, Shenyang 110042, China
3 Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110042; Department of Education, Liaoning Provincial, Key Laboratory of Cancer Etiologic and Prevention, The First Hospital of China Medical University, Shenyang 110001, China
4 Department of Radiotherapy Oncology, The Fourth Hospital of China Medical University, Shenyang 110001, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Yu-Xia Zhao
Department of Radiotherapy Oncology, The Fourth Hospital of China Medical University, No. 4, Chongshan Road, Huanggu District, Shenyang 110001
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.172108

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 > Abstract 

Background: Nonsmall cell lung cancer (NSCLC) mainly contains adenocarcinoma (AC) and squamous cell carcinoma (SqCC). This study investigated single nucleotide polymorphism (SNP) of topoisomerase II alpha (TOP2A) and dual-specificity phosphatase 6 (DUSP6) in a hospital-based case and control cohort of individuals for association with risk of different histological subtypes of NSCLC.
Materials and Methods: A total of 454 (237 SqCC and 217 AC) NSCLC patients, and 454 healthy controls were recruited for analysis of TOP2A rs471692 and DUSP6 rs2279574 genotypes using the TaqMan polymerase chain reaction technique.
Results: TOP2A rs471692 and DUSP6 rs2279574 SNPs were in complete linkage disequilibrium; however, frequency of DUSP6 rs2279574 genotype was significantly different between the case and control, that is, DUSP6 rs2279574a/A and A/C genotypes might contribute to an increased risk of lung squamous carcinoma compared with the C/C genotype. Moreover, DUSP6 rs2279574 AA genotype was also significantly associated with advanced stages of lung cancer. In contrast, frequency of the TOP2A rs471692 genotype had no association between cases and controls (P = 0.906). Genotype frequency of DUSP6 rs2279574 was 11.9% for C/C, 43.6% for C/A, and 44.5% for A/A in the case versus 16.7% C/C, 43.4% C/A, and 39.9% A/A in the control population (χ2 = 3.136, P= 0.077 by Hardy–Weinberg equilibrium test [HWE]). The genotype frequency of TOP2A rs471692 was 50.0% for C/C, 41.6% for C/T, and 8.4% for T/T in the case versus 50.2% C/C, 43.0% C/T, and 6.8% T/T in the control populations (χ2 = 0.023, P= 0.879 by HWE test).
Conclusion: Individuals are carrying DUSP6 rs2279574 AA and AC genotypes associated with an increased risk in developing lung squamous carcinoma in Han Chinese and with advanced NSCLC stages.

Keywords: Dual specificity phosphatase 6, lung cancer, single nucleotide polymorphism, susceptibility, topoisomerase II alpha

How to cite this article:
Wang TL, Song YQ, Ren YW, Zhou BS, Wang HT, Gao Y, Yu H, Zhao YX. Dual-specificity phosphatase 6 genetic variants associated with risk of lung squamous cell carcinoma in Han Chinese. J Can Res Ther 2018;14, Suppl S1:72-8

How to cite this URL:
Wang TL, Song YQ, Ren YW, Zhou BS, Wang HT, Gao Y, Yu H, Zhao YX. Dual-specificity phosphatase 6 genetic variants associated with risk of lung squamous cell carcinoma in Han Chinese. J Can Res Ther [serial online] 2018 [cited 2021 Nov 30];14:72-8. Available from: https://www.cancerjournal.net/text.asp?2018/14/8/72/172108

 > Introduction Top

Lung cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related death in the world.[1] Approximately, 80% of primary lung cancers are nonsmall cell lung cancer (NSCLC) that can further subtypes into adenocarcinoma (AC) and squamous cell carcinoma (SqCC).[2] Epidemiologic studies demonstrated that tobacco smoke accounts for more than 80% of lung cancer cases and more strongly associated with SqCC than with AC; however, less than one-fifth of smokers will develop lung cancer while up to 20% of nonsmokers also suffer from lung cancer in their lifetime.[3],[4] Furthermore, obvious heterogeneity has been observed between different histological subtypes of lung cancer.[5] Previous genome-wide association studies (GWAS) indicate that genetic variations on some chromosome loci may specifically contribute to lung cancer specific histology susceptibility.[6],[7] This support a histology-specific pathogenesis process and biological characteristics of lung cancer. Previous studies [8],[9] showed that the single nucleotide polymorphism (SNP) of gene can alter carcinogen metabolism in the human body and, therefore, influence cell proliferation, cell cycle control, apoptosis, and eventually, tumorigenesis. The risk of lung cancer has been associated with the occurrence of SNPs within different genes,[8],[10],[11] which further confirms that genetic susceptibility and environmental factors differentially affect lung cancer development. DNA topoisomerase II alpha (TOP2A) is a nuclear enzyme that regulates the topologic state of DNA, such as chromosome condensation, chromatic separation, and the relief of tensional stress during gene transcription and DNA replication.[12] Aberrant TOP2A expression or functions associated with cell proliferation [12] and TOP2A overexpression is considered a multi-type cancer marker by a previous meta-analysis of cancer microarray data.[13] Thus, TOP2A SNPs might affect TOP2A transcription and downstream functions, potentially altering cancer susceptibility. Further, as a member of the dual specificity protein phosphatase subfamily, dual-specificity phosphatase 6 (DUSP6) catalyzes active phosphatase proteins and negatively regulates kinases of the MAP kinase superfamily (e.g. MAPK/ERK, SAPK/JNK, and p38). The latter was associated with cell proliferation and differentiation.[14],[15],[16] Previous studies demonstrated that DUSP6 is a tumor suppressor gene whose expression is reduced in several different types of cancers [17] and down-regulation of DUSP6 protein expression enhances human carcinogenesis.[18],[19],[20]

It hypothesized that TOP2A and DUSP6 SNPs could affect lung cancer risk because these two genes encode enzymes that play an important role in cell proliferation-related pathways in lung cancer. Therefore, we detected TOP2A and DUSP6 SNPs in 454 NSCLC cases (237 SqCC and 217 AC) and 454 controls to association with overall susceptibility variants and variants associated with specific histologic types and smoking status.

 > Materials and Methods Top

Study population

This study was approved by the Review Boards of all participating institutions and a written informed consent was obtained from each participant for use of their DNA and clinical data. This study recruited 456 patients diagnosed with NSCLC in our hospital between September 2009 and December 2012. Histologically, these patients were diagnosed with SqCC (237 cases) or AC (219 cases). All patients did not undergo any chemo- or radiotherapy before collection of peripheral blood samples. During the same period of time, 462 healthy individuals were recruited as controls, and did not exhibit any evidence of malignancy during their routine medical examination. These healthy controls were grouped with cancerous cases in terms of gender, age (±5 years), and smoking status. Individuals were considered smokers if they currently or formerly smoked more than 10 packs of tobacco during their lifetime or as nonsmokers if they never smoked tobacco in their lifetime.

All studied individuals were ethnic Han Chinese living in Northern Region of China (Liaoning province and surrounding areas) and were unrelated. The peripheral blood samples were collected, and the complete epidemiological data were collected at the same time.

Single nucleotide polymorphisms selection and genotyping

To select TOP2A and DUSP6 SNPs for this study, we searched the international HapMap database (http://hapmap.ncbi.nlm.nih.gov/) to identify the corresponding sequences, which included 1 kb upstream and downstream from the SNPs. We then downloaded the genotype data only restricted to those of the Han population from Beijing, China (CHB). Thus, we identified two SNPs (rs471692 in TOP2A and rs2279574 in DUSP6) with minor allele frequencies above 1% and a minimum value of 0.8 for the r2 parameter using the tagger algorithm [21] implemented in Haploview version 4.2[22] [Figure 1]. In particular, DUSP6 rs2279574 is localized in exon 1, leading to an amino acid change from Val to Leu. In contrast, TOP2A rs471692 is localized in an intron but does not alter any amino acids of the TOP2A protein.
Figure 1: Genomic localization of TOP2A and dual-specificity phosphatase 6 single nucleotide polymorphism and the linkage disequilibrium structure of the locus. Graphical representation of the genomic structure and location of examined single nucleotide polymorphism sites for TOP2A and dual-specificity phosphatase 6. Exons are denoted by boxes, with untranslated regions in white and translated regions in gray. The linkage disequilibrium structure of the topoisomerase II alpha and dual-specificity phosphatase 6 haplotype block is displayed. Linkage disequilibrium between single nucleotide polymorphisms was analyzed using the pairwise linkage disequilibrium measure D' and r2 and haplotype block was constructed using the solid spine haplotype algorithm (D' <0.8). Each diamond either represents the D' or r2 measure of linkage disequilibrium (r2: Darker shades of black represent greater r2 values)

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To genotype these SNPs, peripheral blood samples (5 ml) of each subject were collected using sodium citrate tubes. DNA was extracted using a standard proteinase K digestion, followed by phenol–chloroform extraction and ethanol precipitation. A TaqMan SNP genotyping assay (Affymetrix Inc., Cleveland, OH, USA) was performed using an Applied Biosystems (ABI) 7500 FAST real-time polymerase chain reaction (PCR) system (Foster City, CA, USA) to genotype each DNA sample. The TaqMan universal PCR master mix and predesigned SNP-genotyping assay mixture containing PCR primers and probes were purchased from ABI. The PCR amplification mixture included 25 μl master mix (ABI), 10 μl of DNA, 2.5 μl of the probe, and 12.5 μl of sterile water. PCR conditions consisted of an initial denaturing step at 95°C for 10 min, followed by 47 cycles of 92°C for 30 s, 60°C for 1 min, and a final extension at 60°C for 1 min. To ensure the accuracy of genotyping, we included three positive controls and two negative controls in each 96-well plate and duplicates of 10% of the testing samples for quality control purposes. The concordance rate was 100% of the duplicate analyses.

Statistical analysis

Hardy–Weinberg equilibrium test (HWE) was performed using a goodness-of-fit Chi-squared test to analyze the distribution of TOP2A and DUSP6 SNPs between case and control. Pearson's Chi-squared test and Student's t-test were separately used to compare the distribution of the demographic variables and examine differences in risk factors and SNP genotypes between case and control. Associations between genotypes and lung cancer risk were estimated by computing odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis with adjustments made for age and smoking status. SPSS 13.0 software (SPSS, Inc. Chicago, IL, USA) was used for all data analyses, and P < 0.05 was considered statistically different. Haplotype frequencies and significance of haplotype association were calculated with Haploview software version 4.2 downloaded from Haploview website (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/downloads). The pair-wise linkage disequilibrium (LD) among the SNP loci of TOP2A and DUSP6, and the HWE test was also assessed using the Haploview software version 4.2.

 > Results Top

Characteristics of study population

Clinical and demographic characteristics are presented in [Table 1]. Specifically, a total of 456 lung cancer patient and 462 healthy control DNA samples were genotyped, but genotyping was unsuccessful for eight patient and two healthy control samples, resulting in 454 patients and 454 controls for data analyses. The median age of these patients was 60-year-old and ranged between 31 and 87-year-old with the majority being male (73.3%). Two hundred and thirty-seven patients were diagnosed with lung SqCC and 217 cases with lung AC. Tumor clinical stages of these patients were I, 51; II, 42; III, 214; and IV, 137 (10 cases had missing data). In contrast, the healthy controls had 310 males with a median age of 56-year-old and ranged between 31 and 87-year-old. There was no statistically significant difference between case and control in terms of gender (P > 0.05), whereas there was a statistically significant difference (P < 0.05) in age and smoking status between case and control.
Table 1: Clinicopathological characteristics of the case and control

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Distribution and cancer risk of topoisomerase II alpha rs471692 and dual-specificity phosphatase 6 rs2279574 single nucleotide polymorphisms between case and control

The data are shown in [Table 2]. In particular, genotype frequency of DUSP6 rs2279574 was 11.9% for C/C, 43.6% for C/A and 44.5% for A/A in the cases versus 16.7% C/C, 43.4% C/A and 39.9% A/A in controls (χ2 = 3.136, P= 0.077 using HWE test). The genotype frequency of TOP2A rs471692 was 50.0% for C/C, 41.6% for C/T and 8.4% for T/T in the cases versus 50.2% C/C, 43.0% C/T and 6.8% T/T in the controls (χ2 = 0.023, P= 0.879 using HWE test). The data were consistent with international HapMap subject data, that is, 0.067 C/C, 0.400 C/A and 0.533 A/A in Han Chinese (CHB) and C (ancestry) allele frequency was 0.267 for DUSP6 rs2279574, while 0.067 C/C, 0.400 C/T and 0.533 T/T in Han Chinese (CHB) and C (ancestry) allele frequency was 0.276 for TOP2A rs471692.
Table 2: Genotype frequency of TOP2A rs471692 and DUSP6 rs2279574 between NSCLC and control

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Logistic regression analysis showed that genotype frequency of DUSP6 rs2279574 was significantly different between groups. Individuals carrying DUSP6 rs2279574 AA genotype had a significantly increased NSCLC risk compared to the carriers with CC genotype in Han Chinese (OR = 1.571, 95% CI = 1.050–2.349). Moreover, NSCLC risk also increased when combining AA and AC genotypes together (OR = 1.489, 95% CI = 1.022–2.169). After adjusting for age and smoking status, the data also showed that carriers of AA and AC genotypes had a significantly increased NSCLC risk compared to carriers of CC genotype, indicating that AA and AC were risk genotypes for NSCLC (P = 0.006, adjusted OR = 1.796, 95% CI = 1.187–2.716). In contrast, there was no statistically significant difference in genotype frequency of TOP2A rs471692 between case and the control populations (P = 0.906, adjusted OR = 0.983, 95% CI = 0.739–1.307).

Association of topoisomerase II alpha rs471692 and dual-specificity phosphatase 6 rs2279574 single nucleotide polymorphisms with clinicopathological data from Nonsmall cell lung cancer patients

Next, we associated TOP2A rs471692 and DUSP6 rs2279574 SNPs with clinic pathological data from NSCLC patients [Table 3]. Tumor histology was used to create a stratified data set, which revealed a statistically significant difference of DUSP6 rs2279574 genotype frequencies between patients with lung squamous carcinoma and the controls. Individuals carrying DUSP6 rs2279574 AA and AC genotypes had a significant increase in risk for NSCLC lung squalors carcinoma compared to CC genotype carriers in Han Chinese (P = 0.062 OR = 1.564, 95% CI = 0.977–2.503). After adjusting for age and tobacco smoke history, significant difference was found between the AA and AC genotypes for risk of lung squamous carcinoma (P = 0.005 adjusted OR = 2.180, 95% CI = 1.263–3.761). However, there was no statistical difference of these genotypes between lung AC and the controls (P = 0.098). Overall, there was no statistical difference of TOP2A rs471692 genotype frequencies between lung squamous carcinoma or AC and the controls (P = 0.786 and P= 0.867, respectively).
Table 3: Genotype frequency of TOP2A rs471692 and DUSP6 rs2279574 between case and control stratified by different tumor pathology

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After that, we performed independent analyses of homogenous samples for Stage I/II versus III/IV patients to investigate the association between the rs2279574 alleles and lung cancer stages [Table 4]. DUSP6 rs2279574 SNPs showed significant allelic homozygote associations with Stage III/IV disease (P = 0.024 OR = 1.659, 95% CI = 1.070–2.571), but not with Stage I/II disease (P = 0.196 OR = 1.603, 95% CI = 0.784–3.280). It also showed a statistically significant difference after adjusting for age between AA genotype and Stage III/IV disease (P = 0.028 adjusted OR = 1.644, 95% CI = 1.056–2.559).
Table 4: Genotype frequency of DUSP6 rs2279574 between case and control stratified by tumor stage

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In addition, we analyzed SNPs data according to tobacco smoke (current and former smokers vs. nonsmokers) between groups [Table 5]. An allele A frequency of DUSP6 rs2279574 showed a significant increase in lung cancer risk in nonsmokers (P = 0.023, adjusted OR = 2.021, 95% CI = 1.103–3.702) and a nonsignificant trend toward increased risk of lung cancer in smokers (P = 0.146, adjusted OR = 1.557, 95% CI = 0.858–2.828). The likelihood ratio test analysis demonstrated that there was no interaction between genotype of DUSP6 rs2279574 and tobacco smoke (P = 0.525). There was not an interaction between genotype and tobacco smoke in lung squamous carcinoma risk by layered analysis according to the different pathological subtypes of NSCLC (P = 0.261).
Table 5: Genotype frequency of DUSP6 rs2279574 between case and control stratified by smoking status

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 > Discussion Top

In this case and control study, we assessed genetic polymorphisms of TOP2A rs471692 and DUSP6 rs2279574 in lung cancer patients for association with the increased risk for developing NSCLC. Our data showed for the 1st time that there was a statistically significant association between DUSP6 rs2279574 polymorphism and lung squamous carcinoma risk. The carriers of the A allele at a locus in DUSP6 rs2279574 had a 1.796 fold higher risk in developing lung cancer than those of the C allele. The data suggested that individuals with transversion of allele C to A have a higher risk in developing lung squamous carcinoma. Moreover, these data were even more significant after adjusted with age and tobacco smoke history. However, TOP2A rs471692 genotype frequency showed no difference in risk of developing NSCLC between case and control. Future studies will investigate how the DUSP6 rs2279574 polymorphism alters the susceptibility of lung cancer risk.

Indeed, the importance of the ERK signaling pathway have been found in lung tumorigenesis.[23]DUSP6 functions as a negative feedback mediator for oncogenic ERK-signaling in NSCLC.[24] However, expression of the DUSP6 protein was mediated by ETS family transcription factors, and the latters are the targets of ERK while knockdown of DUSP6 expression in lung cancer cells significantly increased ERK activation and tumor cell proliferation.[24] Other studies indicated that DUSP6 is a tumor suppressor gene whose expression is reduced in several different types of cancer, including NSCLC.[17],[19],[20],[25] Okudela et al. reported [19] that reduced expression of DUSP6 were associated with increased growth activity and histological grade of primary lung cancers. Loss of heterozygosity of the DUSP6 locus was found in 17.7% of cases and was associated with reduced expression levels.[15] In addition, two studies [20],[25] also showed that the down-regulation of DUSP6 expression was due to epigenetic silencing of DUSP6 or 12q21 allelic loss. Presently, our experiment on DUSP6 rs2279574 SNP may further support these previous studies because individuals carrying rs2279574 AA and AC genotype had a significantly increased risk of NSCLC than carriers with CC genotype. This DUSP6 rs2279574 SNP changes the amino acid Val to Leu. Furthermore, a previous study by Okudela et al.[19] associated the DUSP6 expression with lung AC and SqCC and revealed that DUSP6 expression was reduced in 27.7% (18/65) of lung AC but in 80.8% (21/26) of lung SqCC. Our current data are consistent with this finding and showed that DUSP6 rs2279574 AA genotype contributed higher risk in developing lung SqCC. The risk factors and molecular mechanism of lung AC and SqCC are quite different; for example, SqCC occurs more in tobacco smokers, while lung AC occurs more frequently in female nonsmokers, and tumor lesion localizes at periphery of the lungs.[26] Furthermore, Dong et al.[27] performed a GWAS analysis on 833 lung squamous carcinomas. Three thousand and ninety-four controls followed by a confirmation set of 2223 lung squamous carcinoma cases versus 6409 controls from Chinese populations and found that SLC17A8/NR1H4 rs12296850 at chromosome 12q23.1 was significantly associated with risk of lung squamous carcinoma. Subjects carrying AG or GG genotype had a 26% and 32% decreased the risk of lung squamous carcinoma, respectively as compared to AA genotype. However, no apparent association of rs12296850 with risk of lung AC in a total of 4368 cases with lung AC and 9486 controls. This study suggests that genetic variations on chromosome 12q23.1 may specifically contribute to lung SqCC susceptibility in Chinese populations. Our current study may support this notion because DUSP6 rs2279574 polymorphisms are also localized at chromosome 12q22-23. In addition, a meta-analysis by Amelung et al.[28] showed a common set of genes dysregulated in lung cancer included DUSP6, BPA1, ASCL1, RNAS1, S100P, p63, and CK 5/6 p63, which was able to differentiate lung AC and small cell lung cancer from SqCC. Interestingly, DUSP6 rs2279574 SNP was also reported by the Kim et al. in a totally different context.[29] The Leu114Val and Ser144Ala mutations in DUSP6 proteins, induced by T/G polymorphisms in rs2279574 of exon 1, were shown to induce dominant active function in the reduction of ERK1/2 phosphorylation after lithium treatment. Although this study is nothing to do human cancer, this SNP did affect the response of individual to lithium treatment and altered gene expression; thus, may also affect risk of human cancer. Thus, further study is needed to clarify this SNP in NSCLC.

Furthermore, our current data stratified by tobacco smoke (former or current smokers vs. nonsmokers) in all cases and controls showed that DUSP6 rs2279574 A allele significantly increased risk of lung cancer in nonsmokers but a nonsignificant trend toward increased risk of lung cancer in smokers. The likelihood ratio test demonstrated that there were no interaction between DUSP6 rs2279574 SNP and tobacco smoke (P = 0.525). There was no interaction between DUSP6 rs2279574 SNP and tobacco smoke for the risk of lung squamous carcinoma (P = 0.261). This finding indicates that lung cancers present in smokers and nonsmokers may have adopted different carcinogenic pathways [4] and furthermore, we speculate that genetic variations in DUSP6 might be an additional mechanism causing the reduction or transcriptional deficiency of DUSP6 in lung cancers among nonsmokers. The further detailed investigation will be required to confirm this notion. Moreover, our current data also showed that DUSP6 rs2279574 had a significant allelic homozygote association with lung cancer stage, that is, DUSP6 rs2279574 associated with Stage III/IV disease compared to Stage I/II disease. This finding was comparable with a previous study showing that a significant inverse correlation between DUSP6 expression and the histological grade, T tumor stage.[30] Moreover, another study showed that loss of heterozygosity of DUSP6 exon 1 was associated with a reduced level of DUSP6 expression in NSCLC.[19] Reduced activity of DUSP6 could result in tumor growth advantage and histological grade of the tumor. They also stated that a mutation analysis of the DUSP6 exons in 21 cell lineages and in 48 patient samples did not show any mutation. These results suggest that allelic imbalance in primary lung cancers to be one of the mechanisms mediating the reduction in DUSP6 expression and lost DUSP6 expression could promote progression of lung cancer. Therefore, hypothesized that additional genetic and/or epigenetic alterations are likely the first step for lung neoplasms to develop into advanced forms of cancer and furthermore, we speculated downregulation of DUSP6 associated with cell proliferation, resulting in advanced stages of lung cancer. However, further studies are required to elucidate the underlying mechanisms leading to the association of DUSP6 expression level with tumor progression. In addition, our current study did not show any association of TOP2A rs471692 with lung cancer risk, although a previous study demonstrated that upregulation of TOP2A expression was associated with gastric,[31] breast,[32] ovarian,[33] and lung cancer.[34]TOP2A functions in DNA strand regulation and multiple biochemical steps in chromosome condensation pathways were indeed altered in cancer.[12] These included modifications of histones and aberrations in Holliday junctions.[35],[36] Mitotic cell death could also occur as a result of premature chromosome condensation.[37],[38] We speculate upregulation of TOP2A expression could result in human carcinogenesis. While TOP2A rs471692 is localized in an intron, this genetic variation does not alter any amino acids of the TOP2A protein. Thus, further studies are needed to better understand the role of TOP2A rs471692 in NSCLC risk. According to the HapMap database, TOP2A rs471692 is in LD with 3 other SNPs in the same chromosomal region (rs558068, rs2586112, and rs17680289). For these reasons, TOP2A, which encodes an enzyme and is critical for DNA replication is a suitable candidate for lung cancer susceptibility studies. Moreover, most variants were very rare in the general population and would not be identifiable even in a large sample size; thus, we genotyped TOP2A rs471692 SNP, which is relatively common (7.1% in our population) according to previous data.[9]

It is the first study to demonstrate a statistically significant association between DUSP6 rs2279574 polymorphisms and risk of lung squamous carcinoma in Han Chinese populations. However, this study is considered preliminary, and further study is needed to confirm the data. Moreover, we also acknowledge some restrictions of this case and control study. The main limitations of this study included the fact that the number of some subgroup analyses were small, which decreased the power to detect associations with potential risk factors. Furthermore, the patients enrolled in this study including cases from different therapy centers could bias the result because of confounding clinical conditions.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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