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  • ISSN 1674-8301
  • CN 32-1810/R
Volume 38 Issue 1
Jan.  2024
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Sumeng Wang, Silu Chen, Huiqin Li, Shuai Ben, Tingyu Zhao, Rui Zheng, Meilin Wang, Dongying Gu, Lingxiang Liu. Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS[J]. The Journal of Biomedical Research, 2024, 38(1): 37-50. DOI: 10.7555/JBR.37.20230081
Citation: Sumeng Wang, Silu Chen, Huiqin Li, Shuai Ben, Tingyu Zhao, Rui Zheng, Meilin Wang, Dongying Gu, Lingxiang Liu. Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS[J]. The Journal of Biomedical Research, 2024, 38(1): 37-50. DOI: 10.7555/JBR.37.20230081
shu

Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

  • 1.

    Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China

  • 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, Jiangsu 211166, China

  • 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, Nanjing, Jiangsu 211166, China

  • 4.

    Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China

  • 5.

    Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China

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  • Corresponding author:

    Dongying Gu, Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, China. E-mail: dygu@njmu.edu.cn

    Lingxiang Liu, Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China. E-mail: llxlau@163.com

  • △The authors contributed equally.

  • Received Date: April 06, 2023
  • Revised Date: May 25, 2023
  • Accepted Date: May 27, 2023
  • Available Online: June 02, 2023
  • Published Date: December 17, 2023
    Graphical Abstract
    • Abstract

  • The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis, but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking. To address this gap, we conducted a study aiming to investigate this association and identify relevant biomarkers. We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment, biological activity, and the immune microenvironment. Additionally, we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies (GWASs) involving both East Asian (7062 cases and 195745 controls) and European (24476 cases and 23073 controls) populations. We employed mediation analysis to infer the causal pathway, and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells. Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1 (FEN1) gene were significantly enriched in colorectal tumor tissues, compared with normal tissues. Moreover, a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer (odds ratio = 0.94, 95% confidence interval: 0.90–0.97, Pmeta = 4.70 × 10−9). Importantly, we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors, and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication. In conclusion, this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity, expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

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  • This study was partly supported by the National Natural Science Foundation of China (Grant No. 82173601) and Yili & Jiangsu Joint Institute of Health (Grant No. yl2021ms02).

    We thank the participants who generously gave their help in the study. We also thank the Genetics and Epidemiology of Colorectal Cancer Consortium and Biobank Japan for providing European and East Asian colorectal cancer GWAS data.

    CLC number: R735.3, Document code: A

    The authors reported no conflict of interests.

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