Jiali Xu1, Shengwang Tian2, Zhiqiang Yin3, Shuangshuang Wu4, Lingxiang Liu1, Yingying Qian1, Dong Pei1, Wen Gao1, Jing Xu1, Yongmei Yin1, Ping Liu1, Yongqian Shu5. 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.
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.
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in 3'-untranslated regions of cancer-related genes might affect regulation by microRNAs and contribute to cancerpatients' 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 NSCLCpatients. 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 (TYMSrs2790 and MICArs9266825) 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 NSCLCpatients without surgical operation: rs2790, rs4246215 and rs1882. Further analysis using mRNA expression data from the HapMap suggested that these significant loci (FEN1rs4246215, HDAC2rs11391, MICArs1882 and rs9266825) were closely associated with host genes expression. In vitro functional study for TYMSrs2790 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.
Authors: Karen Toledo-Stuardo; Carolina H Ribeiro; Andrea Canals; Marcela Morales; Valentina Gárate; Jose Rodríguez-Siza; Samantha Tello; Marco Bustamante; Ricardo Armisen; Douglas J Matthies; Gerald Zapata-Torres; Patricio González-Hormazabal; María Carmen Molina Journal: Front Immunol Date: 2021-03-31 Impact factor: 7.561