Nonstop mutations cause loss of renal tumor suppressor proteins <i>VHL</i> and <i>BAP1</i> and affect multiple stages of protein translation

Nonstop extension or stop-loss mutations lead to the extension of a protein at its carboxyl terminus. Recently, nonstop mutations in the tumor suppressor <i>SMAD Family Member 4</i> (<i>SMAD4</i>) have been discovered to lead to proteasomal SMAD4 degradation. However, this mutation type has not been studied in other cancer genes. Here, we explore somatic nonstop mutations in the tumor suppressor genes <i>BRCA1 Associated Protein 1</i> (<i>BAP1</i>) and <i>Von Hippel-Lindau</i> (<i>VHL</i>) enriched in renal cell carcinoma. For <i>BAP1</i>, nonstop mutations generate an extremely long extension. Instead of proteasomal degradation, the extension decreases translation and depletes <i>BAP1</i> messenger RNA from heavy polysomes. For <i>VHL</i>, the short extension leads to proteasomal degradation. Unexpectedly, the mutation alters the selection of the translational start site shifting VHL isoforms. We identify germline <i>VHL</i> nonstop mutations in patients leading to the early onset of severe disease manifestations. In summary, nonstop extension mutations inhibit the expression of renal tumor suppressor genes with pleiotropic effects on translation and protein stability.