Suppressive cancer nonstop extension mutations increase C-terminal hydrophobicity and disrupt evolutionarily...

Area of Science:

• Genomics
• Proteomics
• Cancer Biology

Background:

• Nonstop extension mutations (stop-lost) create proteins with extended C-termini by altering stop codons.
• While SMAD4 nonstop mutations are known in cancer, the effects of others remain largely uncharacterized.

Purpose of the Study:

• To systematically evaluate the impact of 2335 somatic nonstop mutation-derived C-terminal extensions on protein expression across cancers.
• To identify characteristics of effective C-terminal extensions and their relationship to evolutionary patterns.

Main Methods:

• Utilized the pan-cancer NonStopDB dataset for analysis.
• Performed high-throughput screening to assess protein abundance changes.
• Analyzed C-terminal amino acid composition and hydrophobicity.
• Compared cancer-derived extensions with evolutionary conserved C-terminal patterns across species.

Main Results:

• 56.1% of C-terminal extensions significantly reduced protein abundance.
• Effective extensions were identified in tumor suppressor genes including PTEN, APC, B2M, CASP8, CDKN1B, and MLH1.
• Higher hydrophobicity correlated with effective protein destabilization.
• Cancer-derived extensions disrupted conserved evolutionary C-terminal amino acid distribution patterns.

Conclusions:

• Somatic nonstop mutations frequently lead to protein destabilization in cancer.
• C-terminal hydrophobicity is a key determinant of protein destabilization by these extensions.
• Disruption of evolutionary conserved C-terminal features by cancer mutations has functional consequences.