Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA [A375_polyA]

In multiple cancer types, we identified recurrent truncating mutations in ZC3H18 (Z18), a nuclear RNA surveillance component. We show that Z18 truncating (Z18trunc) mutations are oncogenic and that Z18 plays an evolutionarily conserved role in nuclear RNA surveillance of oncogenic ERV RNA.

In zebrafish, Z18trunc accelerated melanoma onset and selectively increased ERV RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia, TCGA melanoma, and TCGA uterine cancer patient samples also expressed higher levels of ERV RNA. In engineered human melanoma cells, Z18trunc enhanced ERV RNA accumulation more than loss of one Z18 allele, indicating dominant negative activity.