Systematic Detection of Alternative Open Reading Frames (altORFs) in Cancer Driver Genes

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Alternative open reading frames (altORFs) expand the coding potential of genes across species.
• Overlapping coding regions are known to occur in mammals.
• The Cancer Gene Census (COSMIC) database contains numerous nucleotide substitutions in cancer genes, potentially harboring uncharacterized altORFs.

Purpose of the Study:

• To identify novel altORFs in human cancer genes using a predictive method.
• To investigate the conservation and origin of these novel altORFs.
• To explore the potential of altORFs as a source of cancer antigens.

Main Methods:

• Utilized a prediction method based on five criteria to detect altORFs in human genes from the COSMIC database.
• Assessed conservation of novel altORFs in mammals.
• Examined altORFs resulting from nucleotide substitutions in primary ORFs.
• Validated findings using mass spectrometry and ribosome profiling data.

Main Results:

• Identified 251 novel altORFs, with 41 highly conserved in mammals.
• Discovered 60 altORFs arising from nucleotide substitutions in cancer gene primary ORFs.
• Found experimental evidence for 38% of the novel altORFs.
• Identified specific altORFs in RET, isocitrate dehydrogenase-2, and TP53 genes.

Conclusions:

• The study identified a significant number of novel altORFs in human cancer genes.
• These altORFs, particularly conserved ones, represent potential novel cancer antigens.
• The findings suggest altORFs could offer new avenues for cancer diagnostics and therapeutics.