Abstract Metastatic melanoma remains a major cause of cancer mortality, underscoring the need to uncover new therapeutic vulnerabilities. Tumor genomic sequencing reveals that nuclear RNA surveillance genes are mutated in a substantial fraction of melanomas, implicating dysregulated RNA metabolism as a potentially important, but still underexplored, driver of tumorigenesis. ERVs and related remnants of ancient viral infections comprise ∼8% of the human genome. Although ERV RNAs trigger immune activation, they are the most abundantly expressed repeat elements in many cancers, suggesting that they provide a selective advantage despite potential immunostimulatory costs. Across multiple cancer types, we identified that ZC3H18 (Z18) —a nuclear RNA surveillance component—is mutated or lost in ∼30% of all cancers and that Z18 has recurrent truncating mutations. We show that Z18 truncating (Z18trunc) mutations are oncogenic and that Z18 plays an evolutionarily conserved role in nuclear surveillance of oncogenic ERV RNA. In zebrafish, Z18trunc accelerated melanoma onset and selectively increased ERV RNA. Z18-mutant CCLE human cancer cell lines and TCGA patient tumors also upregulated ERV RNA. In engineered human melanoma cells, Z18trunc enhanced ERV RNA accumulation more than loss of one Z18 allele, indicating dominant-negative activity. Z18trunc directly stabilized and relocalized ERV RNA to the cytoplasm. Functionally, expression of Z18-regulated zebrafish or human ERV RNA was sufficient to accelerate melanoma in zebrafish and is required for Z18trunc-mediated zebrafish melanoma and human melanoma cell growth. Together, these findings establish a direct, functional role for ERV transcripts in cancer and identify aberrant RNA accumulation—via disrupted nuclear RNA surveillance—as a broad mechanism of oncogenesis and a potential therapeutic vulnerability Citation Format: Tanzina Tanu, Anna Cox, Jennifer Karlow, Priyanka Sharma, Kaiwen Sun, Xueyang He, Andrew McCallion, Kevin Brown, Stephen Chanock, David Liu, Tongwu Zhang, Kathleen Burns, Paul Boutz, Megan L. Insco. RNA as a cancer driver: Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral transcripts abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr SY25-02.
Tanu et al. (Fri,) studied this question.