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Genetic variants in circTUBB interacting with smoking can enhance colorectal cancer risk

  • Genotoxicity and Carcinogenicity
  • Published:
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Abstract

Circular RNAs (circRNAs) are an intriguing class of regulatory RNAs involved in the tumorigenesis of many cancers, including colorectal cancer. Mechanistically, circRNAs sponge microRNAs (miRNAs) with specific miRNA response elements (MREs) and compete for regulatory target genes downstream. However, the genetic effects of MREs on colorectal cancer susceptibility remain unclear. The MREs of colorectal cancer-associated circRNAs (CRC-circRNAs) and corresponding single nucleotide polymorphisms (SNPs) were identified by the transcriptome of cancer cells and the 1000 Genomes Project. The association between candidate SNPs and colorectal cancer risk was evaluated in a Chinese population (1150 cases and 1342 controls) and two European populations (9023 cases and 386,896 controls) using logistic regression analysis. Among the 197 candidate SNPs within MREs of 186 CRC-circRNAs, rs25497 in circTUBB was significantly associated with colorectal cancer risk in a Chinese population after false discovery rate (FDR) correction [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.44–2.21, P = 1.42 × 10–7, PFDR = 2.80 × 10–5] and even reached significance in a genome-wide association study (GWAS) under the dominant model (P = 1.28 × 10–8). Similar results were found in the European populations (ORmeta = 1.30, 95% CI = 1.10–1.53). Both stratification and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk (Pinteraction = 1.48 × 10–2). Here, we first comprehensively identified genetic variants in MREs of CRC-circRNAs and evaluated their effects on colorectal cancer risk in both Chinese and European populations. These findings provide basis for a comprehensive understanding of colorectal cancer etiology.

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Funding

This study was partly supported by National Natural Science Foundation of China (81703307) and the Natural Science Foundation of Jiangsu Province (BK20181371) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

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Author notes

  1. Ke Zhang, Shuwei Li and Dongying Gu contributed equally to the writing of this article.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People’s Republic of China

    Ke Zhang, Yongqian Shu & Lingxiang Liu

  2. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, People’s Republic of China

    Shuwei Li, Kaili Xu, Rui Zheng, Junyi Xin, Yixuan Meng, Shuai Ben, Haiyan Chu, Zhengdong Zhang, Mulong Du & Meilin Wang

  3. Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, People’s Republic of China

    Shuwei Li, Kaili Xu, Rui Zheng, Junyi Xin, Yixuan Meng, Shuai Ben, Haiyan Chu, Zhengdong Zhang & Meilin Wang

  4. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China

    Dongying Gu

  5. Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, People’s Republic of China

    Mulong Du

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  1. Ke Zhang
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  2. Shuwei Li
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Correspondence to Mulong Du, Lingxiang Liu or Meilin Wang.

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Zhang, K., Li, S., Gu, D. et al. Genetic variants in circTUBB interacting with smoking can enhance colorectal cancer risk. Arch Toxicol 94, 325–333 (2020). https://doi.org/10.1007/s00204-019-02624-1

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