Molecular Epidemiology Study On MiRNA Region Polymorphisms And The Susceptibility And Survival Of Lung

Lung cancer is the most commonly diagnosed cancer and also the most common cause of cancer-related death in the world. In China, the incidence and the mortality of lung cancer increased rapidly in the last half century, and are still increasing significantly now. Cigarette smoking is the most important risk factor for lung cancer and the genetic and epigenetic damage caused by tobacco smoke is primarily considered as one of the mechanisms of lung cancer development. Molecular epidemiologic studies showed that there were hundreds of genes involved in lung carcinogenesis, such as p53, Rb and Ras. Although focusing on known genes might yield further understanding in lung cancer development, newly developed markers such as noncoding small RNAs may lead novel insight into the biological mechanisms of lung cancer. microRNAs (miRNAs) are 21- to 24-nucleotide-long small noncoding RNA gene products that regulate gene expression by base pairing with target mRNAs at the 3'-untranslated region(UTR), leading to mRNAs cleavage or translational repression. It has been suggested that miRNAs are involved in various biological processes, including cell proliferation, cell death, stress resistance, and fat metabolism. Moreover, several recent reports show that miRNAs participate in human tumorigenesis as tumor suppressors or oncogenes.Single nucleotide polymorphism (SNP) is the most common genetic variation, and many studies have demonstrated that SNPs are involved in both cancer (including lung cancer) susceptibility and prognosis. Nowadays, a new kind of developed markers named miRNA may break a new path for studying the biological mechanisms of lung cancer. In this study, we searched the miRBase (http://microrna.sanger.ac.uk/targets/) database and finally found the SNPs needed for further studying, then conducted a case-control study and a prospective cohort study respectively to explore the associations between the polymorphisms of miRNA regions and lung cancer susceptibility and survival in Chinese population.Part I miRNA region Polymorphisms and the Survival of Lung Cancer: a Prospective Cohort StudyIn this prospective study we evaluated the associations of miRNA gene region polymorphisms and the survival of lung cancer in a cohort of 663 patients with complete follow-up and clinical information. Our hypothesis was that the SNPs located in miRNA gene and the nearby regions might be related to the survival of lung cancer by influencing the expression of miRNAs. We searched in silicon by blasting 400 miRNA genes and their surrounding sequences with the dbSNP database and identified 273 common (minor allele frequency> 0.05) genetic variants in the Chinese population, then we selected 4 pre-miRNA SNPs rs2910164, rs11614913, rs3746444, rs2292832 (located in hsa-mir-146a, hsa-mir-196a2 , hsa-mir-499, and hsa-mir-149, respectively) and evaluated their associations with the overall survival of NSCLC in a two-stage survival study of Chinese population.In the study, we found that miR-196a2 rs11614913 variant homozygote CC was a significantly unfavorable prognostic factor of NSCLC [Hazard ratio (HR), 1.76; 95%CI (confidence interval), 1.34-2.33]. In the genotype-phenotype correlation analysis using 23 lung cancer tissue samples, rs11614913 CC was associated with a significantly increased mature miR-196a expression in a recessive model (P = 0.037) but not the precursors, suggesting an enhanced processing of pre-miR-196a to its mature form.The results we found tell us that the SNP rs11614913 in miRNA mir-196a2 was associated with the survival in the individuals with NSCLC, and it means that the SNPs residented in miRNA genes and surrounding regions may open new avenues for the studies of prognosis and individual therapeutic interventions of lung cancer. Part II miRNA region Polymorphisms and the Susceptibility to Lung Cancer: a Case-Control StudyThe present study was composed with 1058 histopathologically confirmed incident lung cancer patients and 1035 cancer-free controls. All the controls were randomly selected from a community-based screening program for non-infectious diseases conducted in Jiangsu province during the same time period when the cases were recruited and were frequency-matched to the patients on sex and age. Our hypothesis was that the SNPs located in miRNA genes and the nearby regions might be associated with susceptibility of lung cancer. To test this hypothesis, we performed genotyping analyses for rs11614913 T/C and the other three common SNPs (rs2910164 C/G, rs2292832 C/T, and rs3746444 T/C) located at pre-miRNA regions and evaluated their associations with the susceptibility of lung cancer in a case-control study in Chinese population.We found that miR-196a2 rs11614913 variant homozygote CC was associated with 25% significantly increased risk of lung cancer compared with their wild-type homozygote TT and heterozygote TC (odds ratio, 1.25; 95%CI, 1.01-1.54). However, no significant effects were observed on the association between the other three SNPs and lung cancer risk. The results suggest that the SNP rs11614913 in miR-196a2 could also contribute to lung cancer suseptibility. These findings mean that genetic variation of rs11614913 in miR-196a2 may modulate the risk of developing lung cancer, which may benefit the early screening and the prevention of lung cancer.