title: Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival.
abstract: BACKGROUND
  MicroRNAs (miRs) have an important role in lung carcinogenesis and progression. Single-nucleotide polymorphisms (SNPs) in genes involved in miR biogenesis may affect miR expression in lung tissue and be associated with lung carcinogenesis and progression.
  
  
  METHODS
  we analysed 12 SNPs in POLR2A, RNASEN and DICER1 genes in 1984 cases and 2073 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We investigated miR expression profiles in 165 lung adenocarcinoma (AD) and 125 squamous cell carcinoma tissue samples from the same population. We used logistic and Cox regression models to examine the association of individual genotypes and haplotypes with lung cancer risk and with lung cancer-specific survival, respectively. SNPs-miR expression associations in cases were assessed using two-sample t-tests and global permutation tests.
  
  
  RESULTS
  a haplotype in RNASEN (Drosha) was significantly associated with shorter lung cancer survival (hazard ratio=1.86, 95% CI=1.19-2.92, P=0.007). In AD cases, a SNP within the same haplotype was associated with reduced RNASEN mRNA expression (P=0.013) and with miR expression changes (global P=0.007) of miRs known to be associated with cancer (e.g., let-7 family, miR-21, miR-25, miR-126 and miR15a).
  
  
  CONCLUSIONS
  inherited variation in the miR-processing machinery can affect miR expression levels and lung cancer-specific survival.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Bethesda, MD 20892-7248, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rotunno
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: A W
authors.initials: AW
authors.lastname: Bergen
authors.forename: J
authors.initials: J
authors.lastname: Koshiol
authors.forename: L
authors.initials: L
authors.lastname: Burdette
authors.forename: M
authors.initials: M
authors.lastname: Rubagotti
authors.forename: R I
authors.initials: RI
authors.lastname: Linnoila
authors.forename: F M
authors.initials: FM
authors.lastname: Marincola
authors.forename: P A
authors.initials: PA
authors.lastname: Bertazzi
authors.forename: A C
authors.initials: AC
authors.lastname: Pesatori
authors.forename: N E
authors.initials: NE
authors.lastname: Caporaso
authors.forename: L M
authors.initials: LM
authors.lastname: McShane
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: M T
authors.initials: MT
authors.lastname: Landi
mesh_terms: D053487:DEAD-box RNA Helicases / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D035683:MicroRNAs / Q000032:analysis*; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D043244:Ribonuclease III / Q000235:genetics
chemical_list: D035683:MicroRNAs; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases