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Arch Toxicol. 2018 Aug;92(8):2681-2689. doi: 10.1007/s00204-018-2251-7. Epub 2018 Jul 2.

Circadian clock pathway genes associated with colorectal cancer risk and prognosis.

Gu D1,2, Li S3,4, Ben S3,4, Du M3,5, Chu H3,4, Zhang Z3,4, Wang M6,7, Zhang ZF8, Chen J9.

Author information

1
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210000, Jiangsu, People's Republic of China.
2
Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
3
Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China.
4
Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China.
5
Department of Biostatistics, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China.
6
Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China. mwang@njmu.edu.cn.
7
Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China. mwang@njmu.edu.cn.
8
Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles (UCLA), Los Angeles, CA, USA. zfzhang@ucla.edu.
9
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210000, Jiangsu, People's Republic of China. jinfeichen@sohu.com.

Abstract

Circadian clock genes influence biological processes and may be involved in tumorigenesis. We systematically evaluated genetic variants in the circadian clock pathway genes associated with colorectal cancer risk and survival. We evaluated the association of 119 single nucleotide polymorphisms (SNPs) in 27 circadian clock pathway genes with the risk of colorectal cancer in a case-control study (1150 cases and 1342 controls). The false discovery rate (FDR) method was applied to correct for multiple comparisons. Gene-based analysis was performed by the sequence kernel association test (SKAT). Cox proportional hazards regression was used to calculate the effects of SNPs on the overall survival of patients. We identified that compared to those with the G allele, individuals with the rs76436997 A allele in RORA had a significant 1.33-fold increased risk of colorectal cancer (P = 3.83 × 10- 4). Specifically, the GA/AA genotypes were related to an enhanced risk of colorectal cancer compared with that associated with the GG genotype, which was more common in patients with well and moderately differentiated tumors and Dukes A/B stages. The SNP rs76436997 significantly increased the overall survival time of colorectal cancer patients (P = 0.044). Furthermore, RNA-seq data showed that the mRNA levels of RORA were significantly lower in colorectal tumors than the paired normal tissues. Gene-based analysis revealed a significant association between RORA and colorectal cancer risk. These findings highlight the important roles of genetic variations in circadian clock pathway genes play in colorectal cancer risk and suggest that RORA is potentially related to colorectal carcinogenesis.

KEYWORDS:

Circadian genes; Colorectal cancer; Risk; Survival

PMID:
29968159
DOI:
10.1007/s00204-018-2251-7

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