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

Simone Mocellin,Saveria Tropea,Carlo Riccardo Rossi,Clara Benna

doi:10.1186/s12916-018-1010-1

Simone Mocellin, Saveria Tropea + Show 2 more

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https://doi.org/10.1186/s12916-018-1010-1

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Abstract

BackgroundDysfunction 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).MethodsSingle 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.ResultsWe 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).ConclusionsOur 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.

Highlights

Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, data are scarce and findings inconsistent
The study was composed of three phases: (1) identification of circadian genes; (2) collection of single nucleotide variants of these genes that have been associated with the risk of the three most common malignancies; (3) conduction of adaptive rank truncated product (ARTP)-based gene and pathway analysis based on the P values of circadian gene Single nucleotide polymorphism (SNP) retrieved from Genome-wide association study (GWAS)
We reported the following information: (1) the pathway P value, with the number of SNPs and genes contributing to the pathwaylevel analysis; (2) the gene P value of each gene contributing to the pathway analysis, along with the number of SNPs contributing to the gene-level analysis; (3) the top gene and SNP, defined as the gene and the SNP with the lowest P value from the gene-level analysis and the original GWAS, respectively

Summary

Introduction

Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, data are scarce and findings inconsistent. Circadian rhythms are controlled by what are called circadian pathway genes [2], which have been discovered in all studied species: remarkably, the disruption of these rhythms has been linked to the risk of different diseases such as insomnia, depression, jet leg, stomach ailments, heart attack and cancer [3]. As regards the latter, a growing wealth of evidence supports the potential tumour suppressor role of the biological clock [4]. A single SNP can have an effect too small to be detected by the single locus approach, whereas gene/pathway analysis, which jointly tests multiple SNPs from the same gene/pathway, can more likely identify the association between the outcome and the basic functional unit involved in disease development [8,9,10]

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