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Identification of low-frequency variants of UGT1A3 associated with bladder cancer risk by next-generation sequencing

Oncogene volume 40, pages 2382–2394 (2021)Cite this article

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Abstract

Although genome-wide association studies (GWASs) have successfully revealed many common risk variants for bladder cancer, the heritability is still largely unexplained. We hypothesized that low-frequency variants involved in bladder cancer risk could reveal the unexplained heritability. Next-generation sequencing of 113 patients and 118 controls was conducted on 81 genes/regions of known bladder cancer GWAS loci. A two-stage validation comprising 3,350 cases and 4,005 controls was performed to evaluate the effects of low-frequency variants on bladder cancer risk. Biological experiments and techniques, including electrophoretic mobility shift assays, CRISPR/Cas9, RNA-Seq, and bioinformatics approaches, were performed to assess the potential functions of low-frequency variants. The low-frequency variant rs28898617 was located in the first exon of UGT1A3 and was significantly associated with increased bladder cancer risk (odds ratio = 1.50, P = 3.10 × 10−6). Intriguingly, rs28898617 was only observed in the Asian population, but monomorphism was observed in the European population. The risk-associated G allele of rs28898617 increased UGT1A3 expression, facilitated UGT1A3 transcriptional activity, and enhanced the binding activity. In addition, UGT1A3 deletion significantly inhibited the proliferation, invasion, and migration of bladder cancer cells and xenograft tumor growth. Mechanistically, UGT1A3 induced LAMC2 expression by binding CBP and promoting histone acetylation, which remarkably promoted the progression of bladder cancer. This is the first targeted sequencing study to reveal that the novel low-frequency variant rs28898617 and its associated gene UGT1A3 are involved in bladder cancer development, providing new insights into the genetic architecture of bladder cancer.

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Fig. 1: The producers of the identified low-frequency variant associated with bladder cancer risk.
Fig. 2: The expression pattern of UGT1A3 and allele-specific effect of rs28898617.
Fig. 3: Roles of UGT1A3 knockout in the bladder cancer cellular phenotype.
Fig. 4: The effect of LAMC2 regulation by UGT1A3 on the bladder cancer cellular phenotype.
Fig. 5: Effect of UGT1A3 knockout on tumors in xenograft models.

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Acknowledgements

This study was supported in part by the National Natural Science Foundation of China (81673264) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). We are grateful to all the people who helped us accomplish this project. We thank Genesky Biotechnologies Inc. (Shanghai, China) for providing technical assistance.

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  1. These authors contributed equally: R. Zheng, M. Du, Y. Ge

Authors and Affiliations

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

    Rui Zheng, Mulong Du, Yuqiu Ge, Junyi Xin, Qiuyuan Zhu, Zheng Guo, Shuai Ben, Haiyan Chu, Zhengdong Zhang & Meilin Wang

  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, China

    Rui Zheng, Yuqiu Ge, Fang Gao, Junyi Xin, Qiuyuan Zhu, Zheng Guo, Shuai Ben, Haiyan Chu, Zhengdong Zhang & Meilin Wang

  3. Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China

    Mulong Du

  4. Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, China

    Fang Gao

  5. Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Qiang Lv & Chao Qin

  6. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China

    Yao Zhu, Chengyuan Gu, Mengyun Wang & Dingwei Ye

  7. The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China

    Meilin Wang

  8. Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China

    Meilin Wang

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Contributions

MW and ZZ designed the study and provided supervision. QL, CQ, YZ, CG, MW, and DY recruited study subjects. RZ, MD, YG, and JX performed statistical analyses and summarized results. FG, QZ, ZG, and SB performed functional experiments. RZ, MD, and HC prepared the manuscript.

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Correspondence to Zhengdong Zhang or Meilin Wang.

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Zheng, R., Du, M., Ge, Y. et al. Identification of low-frequency variants of UGT1A3 associated with bladder cancer risk by next-generation sequencing. Oncogene 40, 2382–2394 (2021). https://doi.org/10.1038/s41388-021-01672-1

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