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DNA hypomethylation patterns and their impact on the tumor microenvironment in colorectal cancer

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Abstract

Background

Recent research underscores the pivotal role of immune checkpoints as biomarkers in colorectal cancer (CRC) therapy, highlighting the dynamics of resistance and response to immune checkpoint inhibitors. The impact of epigenetic alterations in CRC, particularly in relation to immune therapy resistance, is not fully understood.

Methods

We integrated a comprehensive dataset encompassing TCGA-COAD, TCGA-READ, and multiple GEO series (GSE14333, GSE37892, GSE41258), along with key epigenetic datasets (TCGA-COAD, TCGA-READ, GSE77718). Hierarchical clustering, based on Euclidean distance and Ward's method, was applied to 330 primary tumor samples to identify distinct clusters. The immune microenvironment was assessed using MCPcounter. Machine learning algorithms were employed to predict DNA methylation patterns and their functional enrichment, in addition to transcriptome expression analysis. Genomic mutation profiles and treatment response assessments were also conducted.

Results

Our analysis delineated a specific tumor cluster with CpG Island (CGI) methylation, termed the Demethylated Phenotype (DMP). DMP was associated with metabolic pathways such as oxidative phosphorylation, implicating increased ATP production efficiency in mitochondria, which contributes to tumor aggressiveness. Furthermore, DMP showed activation of the Myc target pathway, known for tumor immune suppression, and exhibited downregulation in key immune-related pathways, suggesting a tumor microenvironment characterized by diminished immunity and increased fibroblast infiltration. Six potential therapeutic agents—lapatinib, RDEA119, WH.4.023, MG.132, PD.0325901, and AZ628—were identified as effective for the DMP subtype.

Conclusion

This study unveils a novel epigenetic phenotype in CRC linked to resistance against immune checkpoint inhibitors, presenting a significant step toward personalized medicine by suggesting epigenetic classifications as a means to identify ideal candidates for immunotherapy in CRC. Our findings also highlight potential therapeutic agents for the DMP subtype, offering new avenues for tailored CRC treatment strategies.

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Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

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Acknowledgements

Not applicable.

Funding

This research was supported by Medical Products Administration of Guangdong Province (2021YDZ03), the Science and Technology Research Project of Hebei Higher Education Institutions (QN2021012), the National Natural Science Foundation of China (81902498, H2022405002), Hubei Provincial Natural Science Foundation (2019CFB177), Natural Science Foundation of Hubei Provincial Department of Education (Q20182105), Chen Xiao-ping Foundation for the development of science and technology of Hubei Provincial (CXPJJH11800001-2018333), The Foundation of Health and Family planning Commission of Hubei Province (WJ2021Q007), Innovation and entrepreneurship training program (201810929005, 201810929009, 201810929068, 201813249010, S201910929009, S201910929045, S202013249005, S202013249008 and 202010929009) and The Scientific and Technological Project of Taihe hospital (2021JJXM009).

Author information

Author notes

  1. He Huang, Qian Li, Xusheng Tu, Dongyue Yu, Yundong Zhou and Lifei Ma have contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, 510630, China

    He Huang & Chunlian Ke

  2. Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Qian Li

  3. Department of Emergency Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, 510630, China

    Xusheng Tu

  4. College of Life Sciences, Nankai University, Tianjin, China

    Dongyue Yu

  5. Shanghai Medical Innovation Fusion Biomedical Research Center, Shanghai, China

    Yundong Zhou

  6. State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China

    Lifei Ma

  7. College of Lab Medicine, Hebei North University, Zhangjiakou, Hebei, 075000, China

    Lifei Ma

  8. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany

    Kongyuan Wei

  9. Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China

    Yuzhen Gao

  10. Faculty of Hepatopancreatobiliary Surgery, The First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, 100853, China

    Guodong Zhao

  11. State Key Laboratory of Common Mechanism Research for Major Diseas, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Ruiqin Han

  12. Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200000, China

    Fangdie Ye

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  1. He Huang
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  2. Qian Li
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Contributions

C.K., F.Y., and R.H. contributed to the study design and critical revision of the manuscript. H.H., Q.L., X.T., Y.Z., D.Y., and L.M. carried out the study and drafted the manuscript. H.H., Q.L., X.T., Y.Z., D.Y., L.M., Y.G., K.W., and G.Z. analyzed the data. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ruiqin Han, Fangdie Ye or Chunlian Ke.

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Huang, H., Li, Q., Tu, X. et al. DNA hypomethylation patterns and their impact on the tumor microenvironment in colorectal cancer. Cell Oncol. (2024). https://doi.org/10.1007/s13402-024-00933-x

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