2. Academic Validation
  3. Genetic variants in N6-methyladenosine are associated with bladder cancer risk in the Chinese population

Genetic variants in N6-methyladenosine are associated with bladder cancer risk in the Chinese population

  • Arch Toxicol. 2021 Jan;95(1):299-309. doi: 10.1007/s00204-020-02911-2.
Hanting Liu  # 1 2,  Jingjing Gu  # 1 2,  Yu Jin  # 3,  Qi Yuan 1 2,  Gaoxiang Ma 1 2 4,  Mulong Du 1 2,  Yuqiu Ge 1 2,  Chao Qin 5,  Qiang Lv 5,  Guangbo Fu 6,  Meilin Wang 1 2,  Haiyan Chu 7 8,  Lin Yuan 9,  Zhengdong Zhang 10 11
Affiliations

Affiliations

  • 1 Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
  • 2 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, Nanjing, 211166, China.
  • 3 Department of Laboratory Medicine, School of Public Health, Nantong University, Nantong, China.
  • 4 The Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 5 Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 6 Department of Urology, The Affiliated Huai'an First People's Hospital of Nanjing Medical University, Nanjing, China.
  • 7 Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. chy_grape@njmu.edu.cn.
  • 8 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, Nanjing, 211166, China. chy_grape@njmu.edu.cn.
  • 9 Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China. yuanlin47@126.com.
  • 10 Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. drzdzhang@njmu.edu.cn.
  • 11 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, Nanjing, 211166, China. drzdzhang@njmu.edu.cn.
  • # Contributed equally.
PMID: 32964246 DOI: 10.1007/s00204-020-02911-2
Abstract

Recently N6-Methyladenosine (m6A) has been identified to guide the interaction of RNA-binding protein hnRNP C and their target RNAs, which is termed as m6A-switches. We systematically investigated the association between genetic variants in m6A-switches and bladder Cancer risk. A two-stage case-control study was performed to systematically calculate the association of single nucleotide polymorphisms (SNPs) in 2798 m6A-switches with bladder Cancer risk in 3,997 subjects. A logistic regression model was used to assess the effects of SNPs on bladder Cancer risk. A series of experiments were adopted to explore the role of genetic variants of m6A-switches. We identified that rs5746136 (G > A) of SOD2 in m6A-switches was significantly associated with the reduced risk of bladder Cancer (additive model in discovery stage: OR = 0.80, 95% CI 0.69-0.93, P = 3.6 × 10-3; validation stage: adjusted OR = 0.88, 95% CI 0.79-0.99, P = 3.0 × 10-2; combined analysis: adjusted OR = 0.85, 95% CI 0.78-0.93, P = 4.0 × 10-4). The mRNA level of SOD2 was remarkably lower in bladder Cancer tissues than the paired adjacent samples. SNP rs5746136 may affect m6A modification and regulate SOD2 expression by guiding the binding of hnRNP C to SOD2, which played a critical tumor suppressor role in bladder Cancer cells by promoting cell Apoptosis and inhibiting proliferation, migration and invasion. In conclusion, our findings suggest the important role of genetic variants in m6A modification. SOD2 polymorphisms may influence the expression of SOD2 via an m6A-hnRNP C-dependent mechanism and be promising predictors of bladder Cancer risk.

Keywords

Bladder cancer; Molecular epidemiology; N6-methyladenosine; Susceptibility.

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