title: Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis.
abstract: BACKGROUND
  Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.
  
  
  METHODS
  SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate.
  
  
  RESULTS
  Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10(-22) and P = 9.5 × 10(-7), respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10(-4) and P = 2.5 × 10(-4), respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.
  
  
  CONCLUSIONS
  Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. kyle.walsh@ucsf.edu
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.forename: Terri
authors.initials: T
authors.lastname: Rice
authors.forename: Paul A
authors.initials: PA
authors.lastname: Decker
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Kosel
authors.forename: Thomas
authors.initials: T
authors.lastname: Kollmeyer
authors.forename: Helen M
authors.initials: HM
authors.lastname: Hansen
authors.forename: Shichun
authors.initials: S
authors.lastname: Zheng
authors.forename: Lucie S
authors.initials: LS
authors.lastname: McCoy
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.forename: Erik
authors.initials: E
authors.lastname: Anderson
authors.forename: George
authors.initials: G
authors.lastname: Hsuang
authors.forename: Joe L
authors.initials: JL
authors.lastname: Wiemels
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Pico
authors.forename: Ivan
authors.initials: I
authors.lastname: Smirnov
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Berger
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Lachance
authors.forename: Hugues
authors.initials: H
authors.lastname: Sicotte
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D019098:Telomerase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C509186:TERT protein, human; D019098:Telomerase; C532890:RTEL1 protein, human; D004265:DNA Helicases
keywords: age at diagnosis; glioma; single nucleotide polymorphism; telomerase; telomere