Enhancing the utility of Proteomics Signature Profiling (PSP) with Pathway Derived Subnets (PDSs), performance analysis and specialised ontologies.

Background: Proteomics Signature Profiling (PSP) is a novel hit-rate based method that proved useful in resolving consistency and coverage issues in proteomics. As a follow-up study, several points need to be addressed: 1/ PSP's generalisability to pathways, 2/ understanding the biological interplay between significant complexes and pathway subnets co-located on the same pathways on our liver cancer dataset, 3/ understanding PSP's false positive rate and 4/ demonstrating that PSP works on other suitable proteomics datasets as well as expanding PSP's analytical resolution via the use of specialised ontologies.

Results: 1/ PSP performs well with Pathway-Derived Subnets (PDSs). Comparing the performance of PDSs derived from various pathway databases, we find that an integrative approach is best for optimising analytical resolution. Feature selection also confirms that significant PDSs are closely connected to the cancer phenotype.2/ In liver cancer, correlation studies of significant PSP complexes and PDSs co-localised on the same pathways revealed an interesting relationship between the purine metabolism pathway and two other complexes involved in DNA repair. Our work suggests progression to poor stage requires additional mutations that disrupt DNA repair enzymes.3/ False positive analysis reveals that PSP, applied on both complexes and PDSs, is powerful and precise.4/ Via an expert-curated lipid ontology, we uncovered several interesting lipid-associated complexes that could be associated with cancer progression. Of particular interest is the HMGB1-HMGB2-HSC70-ERP60-GAPDH complex which is also involved in DNA repair. We also demonstrated generalisability of PSP using a non-small-cell lung carcinoma data set.

Conclusions: PSP is a powerful and precise technique, capable of identifying biologically coherent features. It works with biological complexes, network-predicted clusters as well as PDSs. Here, an instance of the interplay between significant PDSs and complexes, possibly significantly involved in liver cancer progression but not well understood as yet, is demonstrated. Also demonstrated is the enhancement of PSP's analytical resolution using specialised ontologies.