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The role of polymorphisms in circadian pathway genes in breast tumorigenesis

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Disruption of the circadian rhythm or biological clock, which is regulated by a number of clock genes, including circadian locomotor output cycles kaput (CLOCK), period genes (PERs), and cryptochrome genes (CRYs), is a risk factor for breast cancer. We hypothesized that genetic variation in these clock genes may influence breast cancer risk. To test this hypothesis, we designed a hospital-based study that included 1,538 breast cancer patients and 1,605 healthy controls. We genotyped subjects for five single nucleotide polymorphisms (SNPs) and a length variant of the circadian clock genes and evaluated their associations with breast cancer risk. These polymorphisms were determined by TaqMan allelic discrimination assays and the polymerase chain reaction-restriction fragment length polymorphism method. Univariate logistic regression analysis showed that polymorphisms of the CLOCK and CRY1 genes were associated with breast cancer risk. We found that carriers of the CLOCK CT and combined CT+TT genotypes had a significantly higher risk of breast cancer than carriers of the CC genotype (aOR = 1.35, 95% CI = 1.12-1.63 and aOR = 1.30, 95% CI = 1.09–1.56, respectively). Carriers of the CRY1 GT genotype had a decreased risk of breast cancer (aOR = 0.84, 95% CI = 0.71–0.99). We also observed a lower risk of breast cancer in carriers of the CRY2 CC genotype who were ER-positive than in those who were ER-negative (OR = 0.15, 95% CI = 0.04–0.67). When stratified by the CLOCK genotype, patients with the CLOCK CT/ CRY2 CC genotypes had significantly lower cancer risk than those with the GG genotype (aOR = 0.36, 95% CI = 0.14–0.95). Individuals carrying both the CLOCK CC and PER2 AA genotypes had an increased cancer risk (aOR = 2.28, 95% CI = 1.22–4.26). Our study suggests that genetic variants of the circadian rhythm regulatory pathway genes contribute to the differential risk of developing breast cancer in Chinese populations.

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Abbreviations

CLOCK:

Circadian locomotor output cycles kaput

BMAL1:

Brain and muscle ARNT-like1

SNPs:

Single nucleotide polymorphisms

RFLP:

Restriction fragment length polymorphism

PCR:

Polymerase chain reaction

aORs:

Adjusted odds ratios

CIs:

Confidence intervals

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Acknowledgments

We thank Hongwei Han, Lei Lei, and Yanrui Zhao for their technical assistance. We also thank Ms. Kate Newberry of the Department of Scientific Publications at M. D. Anderson Cancer Center for editing this manuscript. This study was supported partially by grants from the National Natural Science Foundation of China (No. 30771844), the Tianjin Science and Technology Committee Foundation (No. 08ZCGH202000; 09ZCZDSF04400), the Major State Basic Research Development Program of China (973 Program) (No. 2009CB918903), and Tianjin Municipal Science and Technology Commission (No. 08JCZDJC23600). The Tissue Bank is jointly supported by Tianjin Cancer Institute and Hospital and National Foundation for Cancer Research (US).

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, 300060, Tianjin, People’s Republic of China

    Hongji Dai, Lina Zhang, Mingli Cao, Fengju Song, Hong Zheng, Xiaoling Zhu & Kexin Chen

  2. Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Qingyi Wei

  3. Departments of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Wei Zhang

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  1. Hongji Dai
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  2. Lina Zhang
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Correspondence to Kexin Chen.

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Dai, H., Zhang, L., Cao, M. et al. The role of polymorphisms in circadian pathway genes in breast tumorigenesis. Breast Cancer Res Treat 127, 531–540 (2011). https://doi.org/10.1007/s10549-010-1231-2

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