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PubMed · 40680745

Oncogenic roles of young human de novo genes and their potential as neoantigens in cancer immunotherapy.

Chunfu Xiao·Xiaoge Liu·Peiyu Liu·Xinwei Xu·Chao Yao·Chunqiong Li·Qi Xiao·Tiannan Guo·Li Zhang·Yongjun Qian·Chao Wang·Yiting Dong·Yingxuan Wang·Zhi Peng·Chuanhui Han·Qiang Cheng·Ni A An·Chuan-Yun Li
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Abstract

Young human de novo genes, recently emerging from non-coding regions, are expected to contribute to human-specific traits and diseases. However, systematic explorations of this connection have been lacking. Here, we report 37 recently originated de novo genes in humans, with their evolution and characteristics defined within an updated genomic context. The expression of these genes is significantly upregulated and temporospatially expanded in tumors, partially associated with extrachromosomal DNA amplification. Depletion of 57.1% of these genes suppresses tumor cell proliferation, underscoring their roles in tumorigenesis. As a proof of concept, we developed mRNA vaccines expressing ELFN1-AS1 and TYMSOS-young genes specifically expressed during early development but reactivated exclusively in tumors. In humanized mice, these vaccines triggered specific T cell activation and inhibited tumor growth. The antigens derived from these genes are immunogenic and capable of eliciting antigen-specific T cell activation in colorectal cancer patients. These findings underscore young human de novo genes as neoantigens in cancer immunotherapy.

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HumansImmunotherapyAnimalsAntigens, NeoplasmMiceNeoplasmsCancer VaccinesT-LymphocytesOncogenesLymphocyte ActivationCell Line, TumorGene Expression Regulation, NeoplasticColorectal Neoplasmsanti-tumor immunityde novo genesmRNA vaccinesneoantigensJournal ArticleResearch Support, Non-U.S. Gov't

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Chunfu Xiao, Xiaoge Liu, Peiyu Liu, Xinwei Xu, Chao Yao, Chunqiong Li, Qi Xiao, Tiannan Guo, Li Zhang, Yongjun Qian, Chao Wang, Yiting Dong, Yingxuan Wang, Zhi Peng, Chuanhui Han, Qiang Cheng, Ni A An, Chuan-Yun Li. 2025-07-17. Oncogenic roles of young human de novo genes and their potential as neoantigens in cancer immunotherapy.. https://doi.org/10.1016/j.xgen.2025.100928

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