MicroRNA-binding site SNPs in deregulated genes are associated with clinical outcome of non-small cell lung cancer

Jiali Xu; Shengwang Tian; Zhiqiang Yin; Shuangshuang Wu; Lingxiang Liu; Yingying Qian; Dong Pei; Wen Gao; Jing Xu; Yongmei Yin; Ping Liu; Yongqian Shu

doi:10.1016/j.lungcan.2014.06.010

MicroRNA-binding site SNPs in deregulated genes are associated with clinical outcome of non-small cell lung cancer

Lung Cancer. 2014 Sep;85(3):442-8. doi: 10.1016/j.lungcan.2014.06.010. Epub 2014 Jun 21.

Authors

Jiali Xu¹, Shengwang Tian², Zhiqiang Yin³, Shuangshuang Wu⁴, Lingxiang Liu¹, Yingying Qian¹, Dong Pei¹, Wen Gao¹, Jing Xu¹, Yongmei Yin¹, Ping Liu¹, Yongqian Shu⁵

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
² Department of Oncology, Jintan People's Hospital Affiliated to Jiangsu University, Jintan 213200, China.
³ Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
⁴ Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
⁵ Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: shuyongqian@csco.org.cn.

PMID: 24997136
DOI: 10.1016/j.lungcan.2014.06.010

Abstract

Background: Single-nucleotide polymorphisms (SNPs) in 3'-untranslated regions of cancer-related genes might affect regulation by microRNAs and contribute to cancer patients' outcome.

Methods: We used public databases to identify SNPs within miRNA-binding sites in deregulated genes in non-small cell lung cancer (NSCLC). A total of 13 SNPs in 10 genes were included and genotyped by SNaPshot assay in 576 NSCLC patients. Associations between SNPs, overall survival (OS) and chemotherapy response were evaluated by Cox regression and logistic regression. We then examined the functionality of the significant polymorphisms.

Results: Two SNPs (TYMS rs2790 and MICA rs9266825) were significantly associated with OS. In the combined analysis, an increasing number of unfavorable loci was associated with a poorer prognosis (P for trend<0.001) and patients having 2-3 unfavorable loci had a 1.61-fold elevated risk of death (95% confidence interval: 1.20-2.15), compared with those carrying 0-1 unfavorable loci. A significant effect of SNPs on platinum-based chemotherapy response was observed among 296 advanced NSCLC patients without surgical operation: rs2790, rs4246215 and rs1882. Further analysis using mRNA expression data from the HapMap suggested that these significant loci (FEN1 rs4246215, HDAC2 rs11391, MICA rs1882 and rs9266825) were closely associated with host genes expression. In vitro functional study for TYMS rs2790 was carried out. Luciferase assay showed a lower expression level for rs2790 G allele as compared with A allele, and the hsa-miR-1248 had an effect on modulation of TYMS gene.

Conclusion: Our data indicate that miRNA-binding site SNPs in deregulated genes may serve as candidate prognostic markers of NSCLC clinical outcome.

Keywords: Biomarker; Chemotherapy; Non-small cell lung cancer; Outcome; Polymorphism; Survival; miRNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions*
Alleles
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Base Sequence
Binding Sites*
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / mortality*
Cell Line, Tumor
Follow-Up Studies
Genes, Reporter
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / mortality*
MicroRNAs / chemistry
MicroRNAs / genetics*
Patient Outcome Assessment
Polymorphism, Single Nucleotide*
Prognosis
RNA Interference
RNA, Messenger / chemistry
RNA, Messenger / genetics
Transfection

Substances

3' Untranslated Regions
MicroRNAs
RNA, Messenger