Predicting the functional impact of protein mutations: Application to cancer genomics Journal Article
| Authors: | Reva, B.; Antipin, Y.; Sander, C. |
| Article Title: | Predicting the functional impact of protein mutations: Application to cancer genomics |
| Abstract: | As large-scale re-sequencing of genomes reveals many protein mutations, especially in human cancer tissues, prediction of their likely functional impact becomes important practical goal. Here, we introduce a new functional impact score (FIS) for amino acid residue changes using evolutionary conservation patterns. The information in these patterns is derived from aligned families and sub-families of sequence homologs within and between species using combinatorial entropy formalism. The score performs well on a large set of human protein mutations in separating disease-associated variants (∼19200), assumed to be strongly functional, from common polymorphisms (∼35600), assumed to be weakly functional (area under the receiver operating characteristic curve of ∼0.86). In cancer, using recurrence, multiplicity and annotation for ∼10000 mutations in the COSMIC database, the method does well in assigning higher scores to more likely functional mutations ('drivers'). To guide experimental prioritization, we report a list of about 1000 top human cancer genes frequently mutated in one or more cancer types ranked by likely functional impact; and, an additional 1000 candidate cancer genes with rare but likely functional mutations. In addition, we estimate that at least 5 of cancer-relevant mutations involve switch of function, rather than simply loss or gain of function. © 2011 The Author(s). |
| Keywords: | controlled study; gene mutation; gene sequence; mutation, missense; cancer recurrence; validation process; molecular genetics; neoplasms; protein analysis; neoplasm proteins; genetic variability; gene function; prediction; sequence alignment; scoring system; gene loss; genomics; sequence homology; polymorphism, genetic; genetic conservation; genes, p53; genetic polymorphism; receiver operating characteristic; genetic gain; sequence analysis, protein; genetic database; databases, genetic; cancer genomics; genes, neoplasm; entropy; functional impact score |
| Journal Title: | Nucleic Acids Research |
| Volume: | 39 |
| Issue: | 17 |
| ISSN: | 0305-1048 |
| Publisher: | Oxford University Press |
| Date Published: | 2011-09-01 |
| Start Page: | e118 |
| Language: | English |
| DOI: | 10.1093/nar/gkr407 |
| PROVIDER: | scopus |
| PMCID: | PMC3177186 |
| PUBMED: | 21727090 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2011" - "CODEN: NARHA" - "Source: Scopus" |
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