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Nucleic Acids Res. 2014 Oct;42(18):11570-88. doi: 10.1093/nar/gku772. Epub 2014 Sep 17.

Human germline and pan-cancer variomes and their distinct functional profiles.

Author information

1
The Department of Biochemistry & Molecular Medicine, George Washington University Medical Center, Washington, DC 20037, USA.
2
Center for Biologics Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
3
The Department of Biochemistry & Molecular Medicine, George Washington University Medical Center, Washington, DC 20037, USA McCormick Genomic and Proteomic Center, George Washington University, Washington, DC 20037, USA mazumder@gwu.edu.

Abstract

Identification of non-synonymous single nucleotide variations (nsSNVs) has exponentially increased due to advances in Next-Generation Sequencing technologies. The functional impacts of these variations have been difficult to ascertain because the corresponding knowledge about sequence functional sites is quite fragmented. It is clear that mapping of variations to sequence functional features can help us better understand the pathophysiological role of variations. In this study, we investigated the effect of nsSNVs on more than 17 common types of post-translational modification (PTM) sites, active sites and binding sites. Out of 1 705 285 distinct nsSNVs on 259 216 functional sites we identified 38 549 variations that significantly affect 10 major functional sites. Furthermore, we found distinct patterns of site disruptions due to germline and somatic nsSNVs. Pan-cancer analysis across 12 different cancer types led to the identification of 51 genes with 106 nsSNV affected functional sites found in 3 or more cancer types. 13 of the 51 genes overlap with previously identified Significantly Mutated Genes (Nature. 2013 Oct 17;502(7471)). 62 mutations in these 13 genes affecting functional sites such as DNA, ATP binding and various PTM sites occur across several cancers and can be prioritized for additional validation and investigations.

PMID:
25232094
PMCID:
PMC4191387
DOI:
10.1093/nar/gku772
[Indexed for MEDLINE]
Free PMC Article

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