Cancer Causes & Control

, Volume 25, Issue 1, pp 25–32 | Cite as

Circadian pathway genes in relation to glioma risk and outcome

  • Melissa H. Madden
  • Gabriella M. Anic
  • Reid C. Thompson
  • L. Burton Nabors
  • Jeffrey J. Olson
  • James E. Browning
  • Alvaro N. Monteiro
  • Kathleen M. Egan
Original paper



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.


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.


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.


This exploratory analysis provides some evidence supporting a role for circadian genes in the onset of glioma and possibly the outcome of glioma.


Glioma Single nucleotide polymorphism Genotype 



The authors wish to acknowledge the study participants and their families. We further wish to thank the clinicians and research staffs at participating medical centers for their contributions. In addition, we acknowledge Dr. Sajeel A. Chowdhary at Florida Hospital Cancer Institute in Orlando, FL, as well as Harold Colbassani, MD; Dean Gobo, MD; and Christopher Mickler, DO at Morton Plant Mease Healthcare and Baycare Health System in Clearwater, FL, for their efforts recruiting subjects to the study. The project was supported by the National Institutes of Health (R01CA116174) with institutional funding provided by the Moffitt Cancer Center (Tampa, FL) and the Vanderbilt-Ingram Comprehensive Cancer Center (Nashville, TN).

Conflict of interest

The authors have no conflicts of interest.

Supplementary material

10552_2013_305_MOESM1_ESM.docx (33 kb)
Supplementary material 1 (DOCX 33 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Melissa H. Madden
    • 1
  • Gabriella M. Anic
    • 1
  • Reid C. Thompson
    • 2
  • L. Burton Nabors
    • 3
  • Jeffrey J. Olson
    • 4
  • James E. Browning
    • 1
  • Alvaro N. Monteiro
    • 1
  • Kathleen M. Egan
    • 1
  1. 1.Department of Cancer EpidemiologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.Department of Neurological SurgeryVanderbilt University Medical CenterNashvilleUSA
  3. 3.Neuro-oncology ProgramUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Department of NeurosurgeryEmory School of MedicineAtlantaUSA

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