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Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks

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Abstract

Genome-wide association studies (GWASs) have identified over 140 colorectal cancer (CRC)-associated loci; however, target genes at the majority of loci and underlying molecular mechanisms are poorly understood. Here, we utilized a Bayesian approach, integrative risk gene selector (iRIGS), to prioritize risk genes at CRC GWAS loci by integrating multi-omics data. As a result, a total of 105 high-confidence risk genes (HRGs) were identified, which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC. Among the 105 HRGs, CEBPB, located at the 20q13.13 locus, acted as a transcription factor playing critical roles in cancer. Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK, PI3K-Akt, and Ras signaling. Next, by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls, we elucidated that rs1810503, a putative functional variant regulating CEBPB, was associated with CRC risk (OR=0.90, 95%CI=0.86–0.93, P=1.07×10−7). The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls. Mechanistically, the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via long-range promoter-enhancer interactions, mediated by the transcription factor, REST, and thus decreased CRC risk. In summary, our study provides a genetic resource and a generalizable strategy for CRC etiology investigation, and highlights the biological implications of CEBPB in CRC tumorigenesis, shedding new light on the etiology of CRC.

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Acknowledgement

This work was supported by the National Natural Science Foundation of China (82103929, 82273713), Young Elite Scientists Sponsorship Program by CAST (2022QNRC001), Fundamental Research Funds for the Central Universities (WHU:2042022kf1205), Knowledge Innovation Program of Wuhan (whkxjsj011) and Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (ZNJC202207) for Jianbo Tian; Distinguished Young Scholars of China (81925032), Key Program of National Natural Science Foundation of China (82130098), the Leading Talent Program of the Health Commission of Hubei Province, Natural Science Foundation of Hubei Province (2019CFA009) and the Fundamental Research Funds for the Central Universities (2042022rc0026, 2042023kf1005) for Xiaoping Miao; the National Natural Science Foundation of China (82204128) for Xiaoyang Wang. The authors thank the numerous subjects, their families, and referring physicians that have participated in the studies.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China

    Ming Zhang, Xiaoyang Wang, Nan Yang, Zequn Lu, Yimin Cai, Bin Li, Ying Zhu, Jianbo Tian & Xiaoping Miao

  2. Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

    Ming Zhang, Xiaoyang Wang, Nan Yang, Zequn Lu, Yimin Cai, Bin Li, Ying Zhu, Jianbo Tian & Xiaoping Miao

  3. Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China

    Ming Zhang, Xiaoyang Wang, Nan Yang, Zequn Lu, Yimin Cai, Bin Li, Ying Zhu, Jianbo Tian & Xiaoping Miao

  4. Research Center of Public Health, Renmin hospital of Wuhan University, Wuhan University, Wuhan, 430060, China

    Ming Zhang, Nan Yang, Jianbo Tian & Xiaoping Miao

  5. Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, Zhengzhou, 450008, China

    Xiaoyang Wang & Shaokai Zhang

  6. Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Xu Zhu

  7. Department of Radiation Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Xiangpan Li

  8. Department of Gastrointestinal Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430062, China

    Yongchang Wei

  9. Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430073, China

    Xiaoping Miao

  10. Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China

    Xiaoping Miao

Authors
  1. Ming Zhang
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  2. Xiaoyang Wang
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  3. Nan Yang
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  4. Xu Zhu
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  5. Zequn Lu
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  7. Bin Li
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  8. Ying Zhu
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  9. Xiangpan Li
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  10. Yongchang Wei
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  11. Shaokai Zhang
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  12. Jianbo Tian
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  13. Xiaoping Miao
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Corresponding authors

Correspondence to Shaokai Zhang, Jianbo Tian or Xiaoping Miao.

Ethics declarations

The author(s) declare that they have no conflict of interest. The procedures related to human subjects of our study were approved by the Chinese Academy of Medical Sciences Cancer Institute and the institutional review board of Tongji Medical College, Huazhong University of Science and Technology. The study was conducted in accordance with the Helsinki Declaration of 1975 (as revised in 2008).

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Zhang, M., Wang, X., Yang, N. et al. Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks. Sci. China Life Sci. 67, 132–148 (2024). https://doi.org/10.1007/s11427-023-2439-7

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  • DOI: https://doi.org/10.1007/s11427-023-2439-7

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