Pan-cancer analysis of mutation hotspots in protein domains Journal Article


Authors: Miller, M. L.; Reznik, E.; Gauthier, N. P.; Aksoy, B. A.; Korkut, A.; Gao, J.; Ciriello, G.; Schultz, N.; Sander, C.
Article Title: Pan-cancer analysis of mutation hotspots in protein domains
Abstract: Summary In cancer genomics, recurrence of mutations in independent tumor samples is a strong indicator of functional impact. However, rare functional mutations can escape detection by recurrence analysis owing to lack of statistical power. We enhance statistical power by extending the notion of recurrence of mutations from single genes to gene families that share homologous protein domains. Domain mutation analysis also sharpens the functional interpretation of the impact of mutations, as domains more succinctly embody function than entire genes. By mapping mutations in 22 different tumor types to equivalent positions in multiple sequence alignments of domains, we confirm well-known functional mutation hotspots, identify uncharacterized rare variants in one gene that are equivalent to well-characterized mutations in another gene, detect previously unknown mutation hotspots, and provide hypotheses about molecular mechanisms and downstream effects of domain mutations. With the rapid expansion of cancer genomics projects, protein domain hotspot analysis will likely provide many more leads linking mutations in proteins to the cancer phenotype. © 2015 Elsevier Inc.
Journal Title: Cell Systems
Volume: 1
Issue: 3
ISSN: 2405-4712
Publisher: Cell Press  
Date Published: 2015-09-23
Start Page: 197
End Page: 209
Language: English
DOI: 10.1016/j.cels.2015.08.014
PROVIDER: scopus
PMCID: PMC4982675
PUBMED: 27135912
DOI/URL:
Notes: Export Date: 2 October 2015 -- Source: Scopus
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MSK Authors
  1. Martin Lee Miller
    14 Miller
  2. Anil Korkut
    6 Korkut
  3. Chris Sander
    210 Sander
  4. Jianjiong Gao
    132 Gao
  5. Nikolaus D Schultz
    491 Schultz
  6. Bulent Arman Aksoy
    35 Aksoy
  7. Eduard Reznik
    108 Reznik