title: Circadian pathway genes in relation to glioma risk and outcome.
abstract: OBJECTIVE
  There is growing evidence that circadian disruption may alter risk and aggressiveness of cancer. We evaluated common genetic variants in the circadian gene pathway for associations with glioma risk and patient outcome in a US clinic-based case-control study.
  
  
  METHODS
  Subjects were genotyped for 17 candidate single nucleotide polymorphisms in ARNTL, CRY1, CRY2, CSNK1E, KLHL30, NPAS2, PER1, PER3, CLOCK, and MYRIP. Unconditional logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95 % confidence intervals (CI) for glioma risk under three inheritance models (additive, dominant, and recessive). Proportional hazards regression was used to estimate hazard ratios for glioma-related death among 441 patients with high-grade tumors. Survival associations were validated using The Cancer Genome Atlas (TCGA) dataset.
  
  
  RESULTS
  A variant in PER1 (rs2289591) was significantly associated with overall glioma risk (per variant allele OR 0.80; 95 % CI 0.66-0.97; p trend = 0.027). The variant allele for CLOCK rs11133391 under a recessive model increased risk of oligodendroglioma (OR 2.41; 95 % CI 1.31-4.42; p = 0.005), though not other glioma subtypes (p for heterogeneity = 0.0033). The association remained significant after false discovery rate adjustment (p = 0.008). Differential associations by gender were observed for MYRIP rs6599077 and CSNK1E rs1534891 though differences were not significant after adjustment for multiple testing. No consistent mortality associations were identified. Several of the examined genes exhibited differential expression in glioblastoma multiforme versus normal brain in TCGA data (MYRIP, ARNTL, CRY1, KLHL30, PER1, CLOCK, and PER3), and expression of NPAS2 was significantly associated with a poor patient outcome in TCGA patients.
  
  
  CONCLUSIONS
  This exploratory analysis provides some evidence supporting a role for circadian genes in the onset of glioma and possibly the outcome of glioma.
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Madden
authors.forename: Gabriella M
authors.initials: GM
authors.lastname: Anic
authors.forename: Reid C
authors.initials: RC
authors.lastname: Thompson
authors.forename: L Burton
authors.initials: LB
authors.lastname: Nabors
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: James E
authors.initials: JE
authors.lastname: Browning
authors.forename: Alvaro N
authors.initials: AN
authors.lastname: Monteiro
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Egan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000235:genetics*; D005260:Female; D005838:Genotype; D005910:Glioma / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk; D055815:Young Adult