Analysis and Interpretation of the Impact of Missense Variants in Cancer |
| |
Authors: | Maria Petrosino Leonore Novak Alessandra Pasquo Roberta Chiaraluce Paola Turina Emidio Capriotti Valerio Consalvi |
| |
Affiliation: | 1.Dipartimento Scienze Biochimiche “A. Rossi Fanelli”, Sapienza University of Rome, 00185 Roma, Italy; (M.P.); (L.N.); (R.C.);2.ENEA CR Frascati, Diagnostics and Metrology Laboratory FSN-TECFIS-DIM, 00044 Frascati, Italy;3.Dipartimento di Farmacia e Biotecnologie (FaBiT), University of Bologna, 40126 Bologna, Italy; |
| |
Abstract: | Large scale genome sequencing allowed the identification of a massive number of genetic variations, whose impact on human health is still unknown. In this review we analyze, by an in silico-based strategy, the impact of missense variants on cancer-related genes, whose effect on protein stability and function was experimentally determined. We collected a set of 164 variants from 11 proteins to analyze the impact of missense mutations at structural and functional levels, and to assess the performance of state-of-the-art methods (FoldX and Meta-SNP) for predicting protein stability change and pathogenicity. The result of our analysis shows that a combination of experimental data on protein stability and in silico pathogenicity predictions allowed the identification of a subset of variants with a high probability of having a deleterious phenotypic effect, as confirmed by the significant enrichment of the subset in variants annotated in the COSMIC database as putative cancer-driving variants. Our analysis suggests that the integration of experimental and computational approaches may contribute to evaluate the risk for complex disorders and develop more effective treatment strategies. |
| |
Keywords: | protein structure protein stability protein function single amino acid variant putative cancer driving variant free-energy change |
|
|