Analysis and Interpretation of the Impact of Missense Variants in Cancer

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.

Modelling Protein Plasticity: The Example of Frataxin and Its Variants

“…The present work is a further step after the previous bioinformatic [ 13 , 17 ] and simulation works [ 12 , 15 , 18 ] to identify the amino acids relevant to iron and protein binding, respectively.…”

Natural Mutations Affect Structure and Function of gC1q Domain of Otolin-1

“…During the database search, we found many single nucleotide variants (SNVs), including two single nucleotide polymorphisms (SNPs-SNVs with prevalence in the population of 1% or more [7]) in human OTOL1 gene fragment encoding gC1q domain of otolin-1 (hOtolC1q). Then, we checked the position of affected residues in the small angle X-ray scattering (SAXS)-derived model of hOtolC1q trimer [26] and drew suppositions, how the mutations could affect structure and function of hOtolC1q.…”

“…Here, we focus on the missense mutations, which result in a substitution of a single amino acid. Clinically important mutations also involve frameshifts, which have more pronounced effects, insertion-deletion polymorphisms (indels), which result in excision or insertion of a DNA fragment, and mutations involving non-coding sequences, for example introns [6,7]. Typically, the pathogenic missense mutations of the gC1q domain interrupt trimerization, which results in the inability to form biologically active multimers and results in the lack of protein secretion or, in milder cases, secretion of defective, incorrectly folded protein.…”

Molecular Effects of Mutations in Human Genetic Diseases

“…The eight papers published in this SI described case studies that may provide a useful framework for understanding the general molecular defects underlying a broad and diverse spectrum of human diseases. These included multifactorial or polygenic disorders, such as lung cancer (OMIM*612052) and osteoporosis (OMIM*166710) [ 1 , 2 ], or monogenic disorders, such as Long QT Syndrome 1 (LQT; OMIM*192500), Hyaline fibromatosis syndrome (OMIM*228600), Dystrophic epidermolysis bullosa (RDEB; OMIM*226600), Xeroderma Pigmentosum C Phenotype (XP-C; OMIM*278720), and MTHFR deficiency (OMIM*236250) [ 3 , 4 , 5 , 6 , 7 ].…”

“…In the work of Petrosino et al, the performance of state-of-the-art methods for predicting protein stability change and pathogenicity was assessed on a set of 164 cancer-related variants, whose effects on protein stability and function were experimentally determined. Their work suggests that the integration of experimental and computational approaches is crucial to reach significant gains in the prediction of the phenotypic impacts of genomic variations [ 6 ]. For instance, Rocca et al used both sequence and structure analysis, together with pathogenicity and stability predictors to investigate the putative pathogenic role of novel genetic variants identified in a cohort of 128 males with idiopathic low bone mass [ 2 ].…”