title: PIWI-Interacting RNAs in Gliomagenesis: Evidence from Post-GWAS and Functional Analyses.
abstract: PIWI-interacting RNAs (piRNAs), the largest class of noncoding RNAs in mammals, cooperate with PIWI proteins to safeguard the genome from insertional mutations during germline development. Although a growing number of studies have linked the PIWI-piRNA pathway to carcinogenesis, the role of piRNAs in glioma has not been explored.
  
  
  
  Utilizing directly measured and imputed genotypes from the GliomaScan genome-wide association study (1,840 cases and 2,401 controls), genetic variants in 1,428 piRNAs were analyzed for association with glioma risk. In vitro assays were performed to interrogate the functional impact of a top identified piRNA and its variant allele.
  
  
  
  Variants in five piRNAs were considered to be associations of interest and four of these showed narrow clusters of enhanced association signals surrounding the index variant. Functional analyses of one of these piRNAs, piR-598, revealed that transfection of the wild-type piRNA impacted expression of genes involved in cell death/survival and reduced glioma cell viability and colony formation. However, upon delivery of piR-598 containing the variant allele at rs147061479 [OR, 1.80; 95% confidence interval (CI), 1.33-2.46; P = 1.69 × 10(-4)], cell proliferation was sharply increased.
  
  
  
  The genetic association analysis identifies several piRNAs associated with glioma risk, and follow-up functional analyses suggest that variant rs147061479 in piR-598 increases glioma risk by abolishing the tumor-suppressive function of piR-598, instead conferring growth-promoting properties.
  
  
  
  This transdisciplinary study demonstrates a role of piRNAs in gliomagenesis by evidence from both post-GWAS and in vitro functional analyses and supports expanded investigation into the link between the PIWI-piRNA pathway and cancer. Cancer Epidemiol Biomarkers Prev; 25(7); 1073-80. ©2016 AACR.
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Jacobs
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Qin
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lerro
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Alan
authors.initials: A
authors.lastname: Fu
authors.affiliation: Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Robert
authors.initials: R
authors.lastname: Dubrow
authors.affiliation: Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Claus
authors.affiliation: Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: DeWan
authors.affiliation: Department of Genetics, Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Guilin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Yale Stem Cell Center and Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Haifan
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, Connecticut. yong.zhu@yale.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015331:Cohort Studies; D030541:Databases, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: D060565:Argonaute Proteins; D014408:Biomarkers, Tumor; C421088:PIWIL1 protein, human; D034741:RNA, Small Interfering