| Lung cancer is one kind of malignant tumor with top incidence and mortality worldwide. Owing to the sustained growth of tobacco consumption, environment contamination and changes in lifestyle, the epidemic situation of lung cancer has become increasingly serious in our country, and thus it has been one of the major disease which forming a threat to human life and health. Lung cancer can be mainly divided into small cell lung cancer and non-small cell lung cancer (NSCLC), and the latter accounts for about 85% of the total number of lung cancer. Despite the advance of diagnostic and treatment technologies, NSCLC has a very poor prognosis, with the estimated five-year survival rate at about 15% in America,10% in Europe, and 8.9% in developing countries. Currently, NSCLC prognosis prediction and classification are still primarily based on the traditional TNM staging system and pathologic histology. However, when giving the same treatment for some patients with the same clinical staging and pathological type, significant differences between the individual prognosis of cancer do exist, which indicates that different genetic background is one of the important factors affecting the NSCLC survival. As single nucleotide polymorphisms (SNPs) are the main reflection of individual genetic differences, it is of great importance to seek SNPs significantly related to NSCLC and apply them to prognosis prediction, which accordingly could help a lot in guiding individualized treatment and improving the patients’ survival.In recent years, the cancer stem cell (CSC) theory was accepted by many scholars. CSCs are unique cells with the ability of self-renewal and unlimited proliferation, which is crucial to maintain the vitality of tumor cells; meanwhile, their movement and migration make possible the metastasis and recurrence of tumor cells. So far, scientists have made great progress in cancer stem cell research, and specific CSCs and related molecular antigens have already been successfully isolated from NSCLC, breast cancer, colon cancer, liver cancer, and many other tumor tissues. To stem-like cells in NSCLC, they were characterised by the expression of stem cell antigens, such as CD 133, CD 117 and ABCG2; the ability to regenerate the primary tumour; an increased metastatic capability; and drug resistance. Encoded by the CD 133 gene on chromosome 4, CD 133 molecules mainly play a role of transcriptional regulation in the process of development and maturity of cells. Previous studies showed that CD 133 was related to the curative effect, relapse and metastasis of many tumors including lung cancer. Encoded by the CD117 gene on chromosome 4q, CD117 molecules play a crucial regulatory role in many biological processes through combining with ligand stem cell growth factors. Abnormal expression of CD 117 has been found in a variety of human tumor tissues including lung cancer, pancreatic cancer, colon cancer, etc. Besides, CD117 was implicated as a potential oncogene of NSCLC by in vitro experiments in cell line models. Encoded by the ABCG2 gene on chromosome 4q22, ABCG2 is a half ATP-binding cassette (ABC) transporter that facilitates efflux of anticancer drugs from the cells by forming functional dimers, leading to chemotherapy resistance. ABCG2 may serve as a predictor of survival and a molecular target for reducing drug resistance in patients with advanced NSCLC. According to these findings, it was revealed that the three CSC antigens (ABCG2, CD 133 and CD 117) are of great importance in carcinogenesis and cancer prognosis including NSCLC. Various researches have focused on the relationship between expression of three genes (ABCG2, CD133 and CD 117) and NSCLC prognosis; however, systematic analyses on polymorphisms, especially functional polymorphisms in these genes and outcome of NSCLC were scant.Thus, we selected three candidate genes (CD133, CD117 and ABCG2) and screened common polymorphisms (MAF≥0.05) in gene regions (including 10kb up-stream region of each gene) in Han Chinese based on the HapMap database and the HaploView software. After the prediction by using SNPinfo Web Server, Hardy-Weinberg equilibrium analysis and linkage disequilibrium analysis with an r2 threshold of 0.80, we finally included 9 potentially functional SNPs with call rate>90%. We performed a prospective clinical follow-up study in a cohort of 1001 NSCLC patients recruited from the First Affiliated Hospital of Nanjing Medical University and the Cancer Hospital of Jiangsu Province to evaluate the associations between these SNPs and NSCLC survival.We first conducted an association study between baseline characteristics and prognosis of NSCLC, including age, gender, smoking status, histology, clinical stage, surgery status, and hemotherapy or radiotherapy status. The results showed that gender, smoking status, clinical stage, surgery status, and hemotherapy or radiotherapy status were significantly associated with death risk (log-rank P< 0.05). For the analysis of SNPs, CD117 rs2213181 (AA vs GG:adjusted HR= 2.53,95% CI= 1.19-5.36,P=0.016),ABCG2rs3114019(GG vs AA:adjusted HR= 1.59,95% CI= 1.06-2.38, P= 0.024) and ABCG2 rs3114020 (AA vs GG:adjusted HR=1.72, 95% CI= 1.32-2.23, P< 0.001; dominant model:adjusted HR= 1.22,95% CI= 1.02-1.44, P= 0.026; additive model:adjusted HR= 1.25,95% CI= 1.10-1.42, P< 0.001) were associated with unfavorable prognosis of NSCLC with adjustment of age, gender, smoking status, histology, clinical stage, surgery status, and hemotherapy or radiotherapy status. Additionally, ABCG2 rs3114020 remained significant after Bonferroni correction for multiple comparisons (Bonferroni-adjusted P< 0.005). Further stepwise multivariate analysis with demographic characteristics, clinical features and candidate polymorphisms (CD117rs2213181, ABCG2 rs3114019 and ABCG2 rs3114020) showed that rs3114020 G>A was an independent prognostic factor (P= 0.0002). In addition, stratification analysis was carried out by all aforementioned variables, and the results showed that the risk effect of rs3114020 was more pronounced in patients with adenocarcinoma (adjusted HR= 1.40,95%CI =1.20-1.64, P for heterogeneity= 0.044). Moreover, the association between rs3114020 variant genotypes and NSCLC survival was marginally significant in extracted data from TCGA including 805 NSCLC patients (AA vs GG:adjusted HR-1.43,95% CI= 1.00-2.06, P= 0.051; additive model:adjusted HR= 1.19,95% CI = 1.00-1.43, P= 0.055).These findings show that ABCG2 rs3114020 might be an independent biomarker for NSCLC survival in Chinese population, especially among patients with adenocarcinoma. In conclusion, our findings could help to predict NSCLC prognosis, guide individualized treatment, improve the patients’ quality of life and prolong their survival time. |
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