Systematic characterization of pan‐cancer mutation clusters. Issue 3 (25th March 2018)

• Record Type: Journal Article
• Authors: Buljan, Marija; Blattmann, Peter; Aebersold, Ruedi; Boutros, Michael
• Is Part Of: Molecular systems biology. Volume 14:Issue 3(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-03-25
• Subjects: cancer genomics -- hotspot analysis -- interface mutations -- protein complexes; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20177974
• Languages: English
• ISSNs: 1744-4292

Abstract

Abstract: Cancer genome sequencing has shown that driver genes can often be distinguished not only by the elevated mutation frequency but also by specific nucleotide positions that accumulate changes at a high rate. However, properties associated with a residue's potential to drive tumorigenesis when mutated have not yet been systematically investigated. Here, using a novel methodological approach, we identify and characterize a compendium of 180 hotspot residues within 160 human proteins which occur with a significant frequency and are likely to have functionally relevant impact. We find that such mutations (i) are more prominent in proteins that can exist in the on and off state, (ii) reflect the identity of a tumor of origin, and (iii) often localize within interfaces which mediate interactions with other proteins or ligands. Following, we further examine structural data for human protein complexes and identify a number of additional protein interfaces that accumulate cancer mutations at a high rate. Jointly, these analyses suggest that disruption and dysregulation of protein interactions can be instrumental in switching functions of cancer proteins and activating downstream changes. Synopsis: A novel approach is applied to the pan‐cancer data to identify protein residues that accumulate a high fraction of deleterious mutations. An extensive structural and sequence characterization highlights several features associated with these residues. An important fraction of the identified "hotspot residues" map to protein regions that mediate binding to other proteins, nucleic acids or ligands. A significant number of proteins with hotspot residues are tumor suppressors. The approach applied to identify protein hotspot residues, termed DominoEffect, is made available as an R package. In addition, a targeted approach was developed and applied to identify protein interaction interfaces that accumulate cancer mutations at a high rate. Abstract : A novel approach is applied to the pan‐cancer data to identify protein residues that accumulate a high fraction of deleterious mutations. An extensive structural and sequence characterization highlights several features associated with these residues.