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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Article number20
JournalBMC Medicine
Volume16
Issue number1
DOIs
Publication statusPublished - Feb 19 2018

Fingerprint

Genome-Wide Association Study
Lung Neoplasms
Genes
Neoplasms
Prostatic Neoplasms
Breast Neoplasms
Prostate
Breast
Circadian Clocks
Neoplasm Genes
Estrogen Receptors
Single Nucleotide Polymorphism
Meta-Analysis
Squamous Cell Carcinoma
Carcinoma
Lung

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{42738bfea52648e1bffca0f0af97903e,
title = "Circadian pathway genetic variation and cancer risk: Evidence from genome-wide association studies",
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)",
author = "Simone Mocellin and Saveria Tropea and Clara Benna and Rossi, {Carlo Riccardo}",
year = "2018",
month = "2",
day = "19",
doi = "10.1186/s12916-018-1010-1",
language = "English",
volume = "16",
journal = "BMC Medicine",
issn = "1741-7015",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Circadian pathway genetic variation and cancer risk

T2 - Evidence from genome-wide association studies

AU - Mocellin, Simone

AU - Tropea, Saveria

AU - Benna, Clara

AU - Rossi, Carlo Riccardo

PY - 2018/2/19

Y1 - 2018/2/19

N2 - 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.

AB - 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.

KW - Cancer predisposition

KW - Cancer risk

KW - Circadian clock

KW - Gene pathway

KW - Genetic variation

KW - Genome-wide association study (GWAS)

KW - Germline

KW - Pathway analysis

KW - Single nucleotide polymorphism (SNP)

UR - http://www.scopus.com/inward/record.url?scp=85042165871&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042165871&partnerID=8YFLogxK

U2 - 10.1186/s12916-018-1010-1

DO - 10.1186/s12916-018-1010-1

M3 - Article

C2 - 29455641

AN - SCOPUS:85042165871

VL - 16

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

IS - 1

M1 - 20

ER -