Proteogenomics: Opportunities and Caveats

Abstract

Proteogenomics is a rapidly evolving field at the intersection of genomics, transcriptomics, and proteomics. Whole genome, exome, and RNA sequencing are well-established techniques that can provide information at the DNA and RNA level with excellent sequencing coverage and depth. Although tens of thousands of clinical samples have been sequenced thus far, data integration and interpretation still remain largely incomplete. Recent advances in proteomic technologies have enabled the accurate and almost complete characterization of the proteomes of many tissues and biological fluids. Integration of multiomics data for the accurate annotation and reciprocal refinement of genomic and proteomic models is essentially the goal of proteogenomics. This integrative approach has the potential to provide solid evidence for the translation of previously unknown transcripts. Those transcripts and the respective encoded proteins might be implicated in physiological or pathophysiological processes. Novel reported peptides can represent single amino acid variants, splice variants, gene fusions, RNA editing events, novel open reading frames, translated noncoding RNAs, and pseudogenes, among many others. Proteogenomic platforms can now be used to investigate which of these novel “events” gets translated at the protein level, thereby implicating them as candidate new druggable targets or as new diagnostic or prognostic biomarkers for a wide spectrum of diseases. The potential for such identifications is maximized when both sequencing and raw proteomic data originate from the very same sample under investigation. It is becoming clear that this “sample-specific” approach, and the use of matched customized search databases, is associated with lower false-positive and false-negative identification rates. However, like all areas of active research, proteogenomics in its current state is not free of drawbacks. Major limitations in the field are the sensitivity of the mass spectrometers, the increased false discovery rate for the novel peptide hits, and the inherent biophysical properties that render some peptides undetectable. In …