title: Association between glioma susceptibility loci and tumour pathology defines specific molecular etiologies.
abstract: BACKGROUND
  Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) at 7 loci influencing glioma risk: rs2736100 (TERT), rs11979158 and rs2252586 (EGFR), rs4295627 (CCDC26), rs4977756 (CDKN2A/CDKN2B), rs498872 (PHLDB1), and rs6010620 (RTEL1).
  
  
  METHODS
  We studied the relationship among these 7 glioma-risk SNPs and characteristics of tumors from 1374 patients, including grade, IDH (ie IDH1 or IDH2) mutation, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, 9p and 10q loss, and 1p-19q codeletion.
  
  
  RESULTS
  rs2736100 (TERT) and rs6010620 (RTEL1) risk alleles were associated with high-grade disease, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, and 9p and 10q deletion; rs4295627 (CCDC26) and rs498872 (PHLDB1) were associated with low-grade disease, IDH mutation, and 1p-19q codeletion. In contrast, rs4977756 (CDKN2A/B), rs11979158 (EGFR), and to a lesser extent, rs2252586 (EGFR) risk alleles were independent of tumor grade and genetic profile. Adjusting for tumor grade showed a significant association between rs2736100 and IDH status (P = .01), 10q loss (P = .02); rs4295627 and 1p-19q codeletion (P = .04), rs498872 and IDH (P = .02), 9p loss (P = .04), and 10q loss (P = .02). Case-control analyses stratified into 4 molecular classes (defined by 1p-19q status, IDH mutation, and EGFR amplification) showed an association of rs4295627 and rs498872 with IDH-mutated gliomas (P < 10(-3)) and rs2736100 and rs6010620 with IDH wild-type gliomas (P < 10(-3) and P = .03).
  
  
  CONCLUSIONS
  The frequency of EGFR and CDKN2A/B risk alleles were largely independent of tumor genetic profile, whereas TERT, RTEL1, CCDC26, and PHLDB1 variants were associated with different genetic profiles that annotate distinct molecular pathways. Our findings provide further insight into the biological basis of glioma etiology.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière (CRICM), UMR-S975, Paris, France.
authors.forename: Anna Luisa
authors.initials: AL
authors.lastname: Di Stefano
authors.forename: Victor
authors.initials: V
authors.lastname: Enciso-Mora
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.forename: Virginie
authors.initials: V
authors.lastname: Desestret
authors.forename: Marianne
authors.initials: M
authors.lastname: Labussière
authors.forename: Blandine
authors.initials: B
authors.lastname: Boisselier
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.forename: Khe
authors.initials: K
authors.lastname: Hoang-Xuan
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Delattre
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000145:classification / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D002877:Chromosomes, Human / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000145:classification / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor