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2018 ; 14
(3
): e7974
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Systematic characterization of pan-cancer mutation clusters
#MMPMID29572294
Buljan M
; Blattmann P
; Aebersold R
; Boutros M
Mol Syst Biol
2018[Mar]; 14
(3
): e7974
PMID29572294
show ga
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.
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