Understanding the impacts of missense mutations on structures and functions of human cancer-related genes: A preliminary computational analysis of the COSMIC Cancer Gene Census.
View / Open Files
Authors
Alsulami, Ali
Ochoa, Bernardo Montano
Forbes, Simon
Publication Date
2019-01Journal Title
PloS one
ISSN
1932-6203
Publisher
Public Library of Science (PLoS)
Volume
14
Issue
7
Pages
e0219935
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Malhotra, S., Alsulami, A., Heiyun, Y., Ochoa, B. M., Jubb, H., Forbes, S., & Blundell, T. (2019). Understanding the impacts of missense mutations on structures and functions of human cancer-related genes: A preliminary computational analysis of the COSMIC Cancer Gene Census.. PloS one, 14 (7), e0219935. https://doi.org/10.1371/journal.pone.0219935
Abstract
Genomics and genome screening are proving central to the study of cancer. However, a good appreciation of the protein structures coded by cancer genes is also invaluable, especially for the understanding of functions, for assessing ligandability of potential targets, and for designing new drugs. To complement the wealth of information on the genetics of cancer in COSMIC, the most comprehensive database for cancer somatic mutations available, structural information obtained experimentally has been brought together recently in COSMIC-3D. Even where structural information is available for a gene in the Cancer Gene Census, a list of genes in COSMIC with substantial evidence supporting their impacts in cancer, this information is quite often for a single domain in a larger protein or for a single protomer in a multiprotein assembly. Here, we show that over 60% of the genes included in the Cancer Gene Census are predicted to possess multiple domains. Many are also multicomponent and membrane-associated molecular assemblies, with mutations recorded in COSMIC affecting such assemblies. However, only 469 of the gene products have a structure represented in the PDB, and of these only 87 structures have 90-100% coverage over the sequence and 69 have less than 10% coverage. As a first step to bridging gaps in our knowledge in the many cases where individual protein structures and domains are lacking, we discuss our attempts of protein structure modelling using our pipeline and investigating the effects of mutations using two of our in-house methods (SDM2 and mCSM) and identifying potential driver mutations. This allows us to begin to understand the effects of mutations not only on protein stability but also on protein-protein, protein-ligand and protein-nucleic acid interactions. In addition, we consider ways to combine the structural information with the wealth of mutation data available in COSMIC. We discuss the impacts of COSMIC missense mutations on protein structure in order to identify and assess the molecular consequences of cancer-driving mutations.
Keywords
Humans, Neoplasms, Oncogene Proteins, Ligands, Computational Biology, Genomics, Protein Conformation, Structure-Activity Relationship, Mutation, Missense, Models, Molecular, Databases, Genetic, Biomarkers, Tumor
Sponsorship
TLB acknowledges support through his Wellcome Trust Investigator Award 200814/Z/16/Z
Funder references
WELLCOME TRUST (200814/Z/16/Z)
Identifiers
External DOI: https://doi.org/10.1371/journal.pone.0219935
This record's URL: https://www.repository.cam.ac.uk/handle/1810/294913