Original Article The association between SDF-1 G801A polymorphism and non-small cell lung cancer risk in a Chinese Han population

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1 Int J Clin Exp Med 2015;8(8): /ISSN: /IJCEM Original Article The association between SDF-1 G801A polymorphism and non-small cell lung cancer risk in a Chinese Han population Weiguo Xu 1,2, Rong Cui 2, Huapeng Yu 1 1 Department of Respiratory, Zhujiang Hospital, Southern Medical University, Guangzhou, China; 2 Department of Respiratory, Mianyang Central Hospital, Mianyang, China Received March 14, 2015; Accepted May 20, 2015; Epub August 15, 2015; Published August 30, 2015 Abstract: Background: SDF-1 G801A polymorphism is reported to correlate with cancer susceptibility. However, the association between SDF-1 G801A polymorphism and non-small cell lung cancer (NSCLC) risk in Chinese populations remains unknown. Material and methods: A total of 408 NSCLC patients and 303 health controls included in this study. Restriction length fragment polymorphism (RFLP) analysis was used to assess the frequencies of SDF-1 G801A polymorphic variant. Results: No significant association was found between SDF-1 G801A polymorphism and NSCLC risk (OR=1.268, 95% CI , P=0.361). Furthermore, SDF-1 G801A polymorphism was not correlated with histological type (P=0.697) and TNM stage (P=0.276). Conclusion: SDF-1 G801A polymorphism was not a risk factor for NSCLC in Chinese Han population. Keywords: Non-small cell lung cancer, SDF-1, polymorphism, genetics Introduction Lung cancer is the leading cause of cancer death worldwide, and smoking is the major risk factor [1]. Usually diagnosed at an advanced stage, lung cancer is the most common malignancy in China, with the highest mortality rate in male malignancies and the second highest mortality rate in female malignancies. Surgical resection is the most effective treatment and prolongs the survival of patients with early nonsmall cell lung cancer (NSCLC); however, the prognosis for patients with advanced NSCLC is poor, despite recent improvements in chemotherapy and radiotherapy. Improvements in diagnosis are urgently needed to increase the long-term survival of patients with NSCLC. SDF-1, also known as SDF-1, plays an important role in the regulation of hematopoietic cells biological functions such as proliferation, differentiation and migration [2]. In addition, SDF-1 has been showed to closely correlate with tumor growth, angiogenesis, progression and metastasis of various types of cancers [3]. Suzuki et al. found that epigenetic silencing of SDF-1 is a frequent event in NSCLCs, and could be an independent and powerful prognostic marker in patients with NSCLCs and those with stage I disease [4]. Paratore et al. suggested that SDF-1 immunoreactivities could differentiate primary NSCLC with or without brain metastases [5]. Phillips and coworkers also indicated that SDF-1-CXCR4 biological axis is involved in regulating the metastasis of NSCLC [6]. A single nucleotide polymorphism (G to A) exists at position 801 in an evolutionarily conserved segment of the 3 -untranslated region the SDF-1 gene. The G801A polymorphism has been showed to be associated with increased production of SDF-1 transcripts and protein. Moreover, SDF-1 G801A polymorphism has been linked with cancer susceptibility. A significant increase in the GA + AA genotype of the SDF-1 G801A polymorphism was observed in prostate patients in comparison with healthy people. In addition, the prostate patients with SDF-1 G801A polymorphism had a greater extent of lymph node metastasis [7]. Similarly, Razmkhah et al. showed that SDF-1 G801A polymorphism may be regarded as a risk factor

2 Table 1. The clinical feature of the study population Gender Cases (n=408) Controls (n=303) Female 198 (48.53%) 183 (60.40%) Male 213 (51.47) 150 (40.60%) P=0.312 Age 56.3± ±18.2 P=0.234 Smoking status Ever 159 (38.97%) 111 (36.63%) Never 249 (61.03) 192 (63.37%) P=0.658 Family history of cancer Yes 87 (21.32%) 48 (15.84%) No Histology types 315 (78.68%) 255 (84.16%) P=0.534 Squamous cell carcinoma 105 (33.02%) - Adenocarcinoma 303 (66.98%) - TNM stage I 90 (22.06%) - II 96 (23.53%) - III 78 (19.12%) - IV 144 (35.29%) - of increasing the lung cancer and breast cancer susceptibility [8, 9]. Although SDF-1 G801A polymorphism is closely correlated with tumor susceptibility, the genetic effect of SDF-1 G801A polymorphism on NSCLC risk in Chinese populations remains unknown. Therefore, we investigated the association between SDF-1 G801A polymorphisms and NSCLC risk in Chinese Han populations. Methods Study subjects A hospital-based case-control study was conducted in 408 NSCLC patients and 303 cancerfree controls between 2011 and 2014 from Zhujiang Hospital, China (Table 1). All subjects were ethnically homogeneous Chinese Han population and from the city of Guangzhou and its surrounding region. All patients underwent a series of examinations of pathologic stages by board-certified pathologists. Tumor types and stages were determined according to the World Health Organization classification. The controls were randomly selected from healthy individuals who underwent routine physical examination in the same area during the same time period as the case study. Controls had no individual history of cancer. Information on individ- DNA was extracted from peripheral blood by salt extraction. The 3 UTR SDF-1 G801A polymorphism was analyzed using a PCR- RFLP assay and the primers are as follows: sense, 5 -CAGTCAAC- CTGGGCAAAGCC-3 ; antisense, 5 - AGCTTTGGTCCTGAGAGTCC-3. Enzyme digestion followed the identification process. The PCR products were digested with the MspI restriction endonuclease and analyzed by electrophoresis in a 2% agarose gel stained with ethidium bromide and visualized under UV light. Three patterns were observed: a 302-bp band (undigested) for the AA genotype; 302-, 202-, and 100-bp fragments for the AG genotype, and two 202- and 100-bp bands for the GG genotype. Statistical analysis All statistical analyses were performed by the Statistical Package for Social Sciences for Windows software (Windows version release 18.0; SPSS, Inc., Chicago, IL, USA). The frequencies of allele and genotype in cases and controls were calculated by gene counting method. Differences between cases and controls in demographic characteristics and frequencies of genotypes were evaluated by using chi-square (χ 2 ) test. Hardy-Weinberg equilibrium (HWE) was also tested by a chi-square (χ 2 ) test. Differences were considered significant when P<0.05. Results uals was gathered from both cases and controls. The study protocol was approved by the Institutional Review Boards of the hospital. SDF-1 gene polymorphism Genotype frequency distribution was in accordance with the HWE in both patient and control groups. As showed in Table 2, we did not observe a significant difference in the distribution of SDF-1 G801A polymorphic variants in NSCLC patients and controls. The percentage of SDF-1-3 G/G genotypes in NSCLC patients Int J Clin Exp Med 2015;8(8):

3 Table 2. The frequency of SDF-1 genotypes and alleles in patients with NSCLC and health control Total NSCLC Control OR (95% CI) P Genotype GG (59.56%) 201 (66.37%) AG (30.15%) 78 (25.74%) ( ) P=0.361 AA (10.29%) 24 (7.92%) ( ) P=0.532 Allele G (74.63%) 480 (79.21%) - A (25.37%) 126 (20.79%) ( ) P=0.263 Table 3. Prevalence of SDF-1 genotypes compared with histological type and TNM stage Genotype group and control was 59.56% and % respectively. The distribution of the SDF-1-3 A/A genotypes in patients and controls was approximately reached 10.29% and 7.92%, respectively. OR for NSCLC patients with SDF-1-3 A/A genotype was (95% CI= , P=0.523). The frequency of heterozygous SDF-1-3 G/A in patients with NSCLC and controls amounted to 30.15% and 25.74%, respectively. OR of the SDF-1-3 G/A genotypes was ( ), P= In addition, no significant difference about G/A allele distribution was found between NSCLC patients and controls (P=0.263). We also did not observe a significant association between histological type and TNM stage and prevalence of genotypes for the SDF-1-3 G801A polymorphism (Table 3). Discussion Histological type TNM stage SCC AD I II III IV GG AG AA P=0.697 P=0.276 SCC, Squamous cell carcinoma; AD, Adenocarcinoma. Lung cancer is a leading cause of cancer mortality and disease burden worldwide, with the vast majority of lung cancers present as advanced on diagnosis [10]. Various risk factors for development of lung cancer have been identified, including exposure to physical (radon), chemical (smoking, cooking oil fumes and indoor coal burning) and biological (HPV, Mycobacterium tuberculosis) carcinogens [11]. Recent studies have shown that genetic instability also contributes to development of lung cancer. For example, positive family history is an independent risk for this tumor and recent studies have identified SNP polymorphisms in individual genes or mirnas associated with increased risk for lung cancer development [12]. In the present study, our results showed that no significant difference in the distribution of the SDF-1-G801A gene variant was found between patients with NSCLC and healthy individuals. In addition, SDF-1-G801A genotype was not correlated with histological type and TNM stage, suggesting that SDF-1-G801A polymorphism may be not a risk factor for NSCLC. Contradictory with our study, AA and AG genotypes of SDF are considered as factors increasing the susceptibility of Iranian women to breast cancer and lung cancer [8, 9]. A significant increase in the GA and AA subgroups was observed in colorectal cancer patients compared with healthy controls [13]. In addition, the frequency of SDF-1-G801A genotype was vastly increased among older colorectal cancer patients, suggesting that SDF-1-G801A may be a risk factor for colorectal cancer in Taiwanese patients [14]. Chang also found that the SDF-1-G801A polymorphism was associated with local lymph node metastasis in colorectal cancer [15]. The frequencies of the AG and AA genotypes of SDF-1 were significantly higher in patients with benign salivary gland tumors than in the healthy people [16]. Although no statistically significance of SDF-1-G801A polymorphism distribution was found between oral cancer patients and health control. SDF-1- G801A polymorphism is associated with advanced stages of oral cancer and alcohol abuse. However, consistent with our study, various study showed that SDF-1 G801A polymorphism was not associated with cancer risk. There was Int J Clin Exp Med 2015;8(8):

4 no significant difference about the distribution of AA, AG, and GG genotypes of SDF in patients with transitional cell carcinoma of the bladder and health people [17]. No difference about the frequency of the SDF A allele was found between malignant salivary gland tumors and controls [15]. Compared with the homozygous GG subgroup, GA and AA subgroups do not have a higher risk of cervical neoplastic lesions of uterine cervix [18]. Similarly, no significant association was found between wild and heterozygous genotypes regarding clinical, laboratory data, malignant cell dissemination and tissue infiltration in patients with acute myeloid leukemias or chronic myeloid leukemias [19]. SDF-1 G801A polymorphism was not associated with colorectal and gastric cancers in Southern Iranian patients [20]. SDF- 1-3 A gene variant was showed to be not a risk factor for breast cancer incidence in Polish population [21]. The conflicting results about the role of SDF-1 G801A polymorphism in cancers may due to the different types of cancers and the various ethnic populations. Further and larger scale studies are needed to perform to find out the correlation between SDF-1 G801A polymorphism and NSCLC risk in other various populations. In conclusion, the current study showed that SDF-1 G801A polymorphism could not impact the risk of NSCLC in a Chinese Han population. Disclosure of conflict of interest None. Address correspondence to: Huapeng Yu, Department of Respiratory, Zhujiang Hospital, Southern Medical University, No. 253 Gongye Road, Guangzhou , China. Tel: ; yuhuapengguangzhou@163.com References [1] Siegel R, Naishadham D and Jemal A. Cancer statistics, CA Cancer J Clin 2012; 62: [2] Broxmeyer HE, Kim CH, Cooper SH, Hangoc G, Hromas R, Pelus LM. Effects of CC, CXC, C, and CX3C chemokines on proliferation of myeloid progenitor cells, and insights into SDF-1- induced chemotaxis of progenitors. Ann N Y Acad Sci 1999; 872: [3] Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cellderived factor 1 (SDF-1). J Exp Med 1999; 184: [4] Suzuki M, Mohamed S, Nakajima T, Kubo R, Tian L, Fujiwara T, Suzuki H, Nagato K, Chiyo M, Motohashi S, Yasufuku K, Iyoda A, Yoshida S, Sekine Y, Shibuya K, Hiroshima K, Nakatani Y, Yoshino I, Fujisawa T. Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis. Int J Oncol 2008; 33: [5] Paratore S, Banna GL, D Arrigo M, Saita S, Iemmolo R, Lucenti L, Bellia D, Lipari H, Buscarino C, Cunsolo R, Cavallaro S. CXCR4 and CXCL12 immunoreactivities differentiate primary non-small-cell lung cancer with or without brain metastases. Cancer Biomark ; 10: [6] Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP, Strieter RM. The stromal derived factor-1/cxcl12-cxc chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med 2003; 167: [7] Hirata H1, Hinoda Y, Kikuno N, Kawamoto K, Dahiya AV, Suehiro Y, Tanaka Y, Dahiya R. CXCL12 G801A polymorphism is a risk factor for sporadic prostate cancer susceptibility. Clin Cancer Res 2007; 13: [8] Razmkhah M, Talei AR, Doroudchi M, Khalili- Azad T, Ghaderi A. Stromal cell-derived factor-1 (SDF-1) alleles and susceptibility to breast carcinoma. Cancer Lett 2005; 225: [9] Razmkhah M, Doroudchi M, Ghayumi SM, Erfani N, Ghaderi A. Stromal cell-derived factor-1 (SDF-1) gene and susceptibility of Iranian patients with lung cancer. Lung Cancer 2005; 49: [10] Slatore CG, Sullivan DR, Pappas M, Humphrey LL. Patient-centered outcomes among lung cancer screening recipients with computed tomography: a systematic review. J Thorac Oncol 2014; 9: [11] Hasegawa Y. Lung cancer: progress in diagnosis and treatments. Topics: I. Epidemiology and pathogenesis; 2. The etiology of lung cancer. Nihon Naika Gakkai Zasshi 2014; 103: [12] Zhao Y, Wei Q, Hu L, Chen F, Hu Z, Heist RS, Su L, Amos CI, Shen H, Christiani DC. Polymorphisms in MicroRNAs are associated with survival in non-small cell lung cancer. Cancer Epidemiol Biomarkers Prev 2014; 23: [13] Shi MD, Chen JH, Sung HT, Lee JS, Tsai LY, Lin HH. CXCL12-G801A polymorphism modulates risk of colorectal cancer in Taiwan. Arch Med Sci 2013; 9: [14] Chang SC, Lin PC, Yang SH, Wang HS, Li AF, Lin JK. SDF-1alpha G801A polymorphism predicts lymph node metastasis in stage T3 colorectal cancer. Ann Surg Oncol 2009; 16: Int J Clin Exp Med 2015;8(8):

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