Systematic Characterization of Mutations Altering Protein Degradation in Human Cancers

Summary: The Ubiquitin-Proteasome System (UPS) is the primary route for selective protein degradation in human cells. The UPS represents an attractive target for novel cancer therapeutics, but the precise UPS genes and substrates important for cancer growth are incompletely understood. Leveraging multi-omics data across more than 9,000 human tumors and 33 cancer types, we found that over 19% of all cancer driver genes impact UPS function. We implicate transcription factors as important substrates, and show that c-Myc stability is modulated by CUL3. Moreover, we developed a deep learning model (deepDegron) to identify mutations that result in degron loss, and experimentally validated predictions that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability. Lastly, we identified UPS driver genes associated with patient prognosis and the tumor microenvironment. This study demonstrates the important role of UPS dysregulation in human cancers and underscores the potential therapeutic utility of targeting the UPS.

Data: The data.tar.gz file contains all of the necessary raw data and plots created in the manuscript. The dataset is meant to be used with our code that has been deposited on github as jupyter notebooks (https://github.com/ctokheim/Tokheim_2019). The original_films.zip contains all raw gel pictures shown in the manuscript.