Elsevier

Lung Cancer

Volume 94, April 2016, Pages 15-21
Lung Cancer

Association between polymorphisms in pre-miRNA genes and risk of lung cancer in a Chinese non-smoking female population

https://doi.org/10.1016/j.lungcan.2016.01.013Get rights and content

Highlights

  • SNPs in miR-146a and miR-423 are associated with lung cancer in nonsmoking females.

  • MiR-196a2, miR-30c-1, miR-608 and miR-27a SNPs are not associated with lung cancer.

  • MiR-146a, miR-423, miR-608 and miR-27a SNPs are associated with lung adenocarcinoma.

  • There was not an interaction of miR-146a and miR-423 polymorphisms on lung cancer.

Abstract

Background

MicroRNAs play important roles in the development of human chronic diseases including lung cancer. This is the first case-control study of lung cancer in a non-smoking female population in northeast China, to evaluate the roles of the polymorphisms in pre-miRNAs on risk of lung cancer.

Methods

The genotypes of six polymorphisms in miRNAs were determined in 575 patients with lung cancer and 608 healthy controls who were frequency matched for age.

Results

For miR-146a rs2910164, individuals carrying heterozygous CG or homozygous GG genotype had decreased risks of lung cancer compared with those carrying homozygous wild CC genotype (adjusted odds ratios were 0.76 and 0.64, 95% confidence intervals were 0.59–0.99 and 0.46–0.90, P values were 0.039 and 0.010, respectively). G allele of rs2910164 was associated with a lower risk of lung cancer with a significant odds ratio of 0.80. MiR-423 rs6505162CA or AA genotype was associated with significantly decreased risk for lung cancer compared to CC genotype (adjusted odds ratios were 0.77 and 0.54). The significant result was also found in the allele model with odds ratio of 0.75. However, miR-196a2 rs11614913, miR-30c-1 rs928508, miR-608 rs4919510 and miR-27a rs895819 polymorphisms were not significantly associated with lung cancer risks in any models. The similar results were also found in lung adenocarcinoma patients.

Conclusions

These findings suggest that miR-146a rs2910164C>G and miR-423 rs6505162C>A polymorphisms may contribute to genetic susceptibility to lung cancer and lung adenocarcinoma in Chinese non-smoking females.

Introduction

In China, lung cancer is currently the most common cancer among men and the second one among women and is the leading cause of cancer-related deaths for both genders. The incidence and mortality rate of lung cancer in China urban populations have reached the number one among malignant tumors. It is well known that smoking is the predominant risk factor for lung cancer. However, not all lung cancer patients have a history of smoking, it is estimated that 15% male and 53% female of lung cancer patients are nonsmokers [1], which suggests that in addition to tobacco, other risk factors are likely involved in the etiology of lung cancer. The epidemiologic characteristics and risk factors of lung cancer in nonsmokers are not clear. Over past 20 years, it is estimated that the incidence of male and female lung cancer cases increased by 44% and 76% respectively [2]. The incidence of lung cancer among female population is still growing and close to the peak in males. Some studies suggested that females are more likely than males to have non-smoking-associated lung cancer [3]. So in this sense it is more important to study the impact factors of lung cancer in non-smoking females.

Molecular epidemiologic studies showed that there were hundreds of genes involved in lung carcinogenesis [4], in which some were basely confirmed such as p53, Rb, and Ras and there were also some new genes. Although studying known genes could help to further understand the development of lung cancer, newly developed markers such as noncoding small RNAs may lead novel insight into the molecular mechanisms that contribute to lung cancer [5]. Emerging evidence supports a role for microRNAs (miRNAs) in lung cancer development and/or progression. MiRNAs are a class of new non-coding RNAs of approximately 20 nucleotides in length, which are considered to regulate expression by binding to cis-regulatory regions of 3′-UTR regions of genes, restrain the translation of genes at post-transcription level [6]. MiRNAs have been implicated in crucial biological processes, including development, differentiation, apoptosis, proliferation and various diseases including cancer [7]. The study showed that more than 50% of miRNA genes located in cancer-associated genomic regions or in fragile sites, suggesting that miRNAs may play an important role in the pathogenesis of human cancers [8].

In recent years, much attention of genetic susceptibility studies of cancer have been focused on single nucleotide polymorphisms (SNPs) in candidate genes. SNPs in miRNA containing genomic regions have been reported to be rare and unlikely to be functionally important [9]. However, Duan et al. and Gottwein et al. identified SNPs within the seed region or in the precursor stem-loop of miR miRNA may significantly affect the production or processing of miRNA [10], [11]. These lines of evidence suggest that sequence variations affect the expression or function of their host miRNAs. Now the researchers conclude that SNP or mutations in miRNA sequence may alter expression, maturation and/or target selection of miRNA, and consequently contribute to modified cancer risk. In late years, the association between polymorphisms presents in flanking regions of miRNAs and the risk of cancer has become the hot topic in cancer etiology research. However, the effect of the SNPs in miRNAs on the susceptibility of lung cancer in non-smoking females has not been reported so far. To our knowledge, this is the first case-control study of lung cancer in a non-smoking female population in northeast China, to evaluate the roles of the SNPs in pre-miRNAs on risk of lung cancer.

Section snippets

Study subjects

This is an ongoing molecular epidemiologic study of lung cancer in Shenyang City, located in northeast China. In this hospital-based case-control study, the case group consisted of 575 diagnosed nonsmoking female lung cancer patients (between July 2010 and December 2012) at Shenyang Northern Hospital, The First Affiliated Hospital of China Medical University, Liaoning Cancer Hospital & Institute and et al. The inclusions of case group were: (a) newly diagnosed with histologically confirmed lung

Results

There are 575 cases and 608 controls. All individuals were nonsmoking females. The mean ages were 57.1 ± 11.8 and 56.4 ± 13.1 in case and control group, respectively. There were no difference in age between cases and controls (t = −1.080, P = 0.280). Of the 575 lung cancer cases, 390 (67.83%) patients were adenocarcinoma, 101 (17.57%) were squamous cells carcinoma and 84 (14.60%) were other types. The genotype distributions of the six SNPs in the cases and controls are shown in Table 1. The observed

Discussion

In the present study, we evaluated the association between six functional polymorphisms in six miRNAs and lung cancer risks in a Chinese non-smoking female population of 575 incident lung cancer cases and 608 controls. To the best of our knowledge, this is the first study presenting the role of these six pre-miRNA polymorphisms together in the etiology of lung cancer, as well as their interaction in Chinese non-smoking females. Our findings suggest that the rs2910164CG/GG genotypes in miR-146a

Conclusions

The miR-146a rs2910164C>G and miR-423 rs6505162C>A polymorphisms may contribute to genetic susceptibility to lung cancer and lung adenocarcinoma in Chinese non-smoking females.

Role of the funding

The funding source provided the reagents for polymorphism testing and had no involvement in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication.

This study was supported by National Natural Science Foundation of China (No. 81102194).

Conflict of interests

The authors declare that they have no conflict of interests.

Acknowledgements

We are grateful to patients for their participation. We would like to thank all the personnel at the hospitals in our study. This study was supported by National Natural Science Foundation of China (No. 81102194).

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