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Meta-Analysis
. 2018 Feb 19;16(1):20.
doi: 10.1186/s12916-018-1010-1.

Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies

Simone Mocellin  1   2 , Saveria Tropea  3 , Clara Benna  4 , Carlo Riccardo Rossi  4   3
Affiliations
Meta-Analysis

Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies

Simone Mocellin et al. BMC Med. .

Abstract

Background: Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs).

Methods: Single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n = 15,748; controls, n = 18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n = 14,160; controls, n = 12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n = 12,160; controls, n = 16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma.

Results: We found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value = 1.9 × 10-6; top gene RORA, gene P value = 0.0003), prostate (pathway P value = 4.1 × 10-6; top gene ARNTL, gene P value = 0.0002) and lung cancer (pathway P value = 6.9 × 10-7; top gene RORA, gene P value = 2.0 × 10-6), as well as all their subgroups. Out of 17 genes investigated, 15 were found to be significantly associated with the risk of cancer: four genes were shared by all three malignancies (ARNTL, CLOCK, RORA and RORB), two by breast and lung cancer (CRY1 and CRY2) and three by prostate and lung cancer (NPAS2, NR1D1 and PER3), whereas four genes were specific for lung cancer (ARNTL2, CSNK1E, NR1D2 and PER2) and two for breast cancer (PER1, RORC).

Conclusions: Our findings, based on the largest series ever utilized for ARTP-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition.

Keywords: Cancer predisposition; Cancer risk; Circadian clock; Gene pathway; Genetic variation; Genome-wide association study (GWAS); Germline; Pathway analysis; Single nucleotide polymorphism (SNP).

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No ethical committee approval was required.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Schematic view of the circadian pathway. CLOCK and NPAS2 form heterodimers with ARNTL (also known as BMAL1) or ARNTL2 (BMAL2); these heterodimers act as transcription factors binding to enhancer box (E-box) elements upstream of target genes. Besides the clock-controlled genes (CCGs), which mediate the circadian pathway physiological functions, CLOCK and NPAS2 activate the transcription of other core circadian genes such as PER1, PER2, PER3 and CRY1, CRY2. PER and CRY proteins heterodimerize and activate a negative feedback loop acting directly on CLOCK and NPAS2. The activity of PER and CRY proteins is also regulated by additional proteins such as CSNK1E and CSNK1D (inhibition) and TIMELESS (unclear effect), respectively. CLOCK and NPAS2 also transactivate the expression of other pathway components such as NR1D1, NR1D2 (also known as REV-ERBs) and RORA, RORB and RORC (which are transcription factors acting through ROR/REV-ERB elements): these proteins can inhibit or enhance ARNTL transcription, respectively, which adds a further level of modulation of CLOCK/NPAS2 activity. Green lines, stimulatory effect (positive loop); red lines, inhibitory effect (negative loop)
Fig. 2
Fig. 2
Venn diagram showing the genes selected by pathway analysis as statistically significantly associated with the risk of one, two or three types of cancer considered in this study
See this image and copyright information in PMC

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