Protein-structure-guided discovery of functional mutations across 19 cancer types.
Local concentrations of mutations are well known in human cancers. However, their three-dimensional spatial relationships in the encoded protein have yet to be systematically explored. We developed a computational tool, HotSpot3D, to identify such spatial hotspots (clusters) and to interpret the potential function of variants within them. We applied HotSpot3D to >4,400 TCGA tumors across 19 cancer types, discovering >6,000 intra- and intermolecular clusters, some of which showed tumor and/or tissue specificity. In addition, we identified 369 rare mutations in genes including TP53, PTEN, VHL, EGFR, and FBXW7 and 99 medium-recurrence mutations in genes such as RUNX1, MTOR, CA3, PI3, and PTPN11, all mapping within clusters having potential functional implications. As a proof of concept, we validated our predictions in EGFR using high-throughput phosphorylation data and cell-line-based experimental evaluation. Finally, mutation-drug cluster and network analysis predicted over 800 promising candidates for druggable mutations, raising new possibilities for designing personalized treatments for patients carrying specific mutations.
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
Beifang
B
Niu
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Adam D
AD
Scott
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Sohini
S
Sengupta
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Matthew H
MH
Bailey
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
Prag
P
Batra
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Jie
J
Ning
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Matthew A
0000-0003-4197-551X
MA
Wyczalkowski
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Wen-Wei
WW
Liang
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Department of Genetics, Washington University, St. Louis, Missouri, USA.
Qunyuan
Q
Zhang
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
Michael D
MD
McLellan
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Sam Q
SQ
Sun
Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Piyush
P
Tripathi
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Carolyn
C
Lou
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Department of Genetics, Washington University, St. Louis, Missouri, USA.
Kai
K
Ye
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.
R Jay
RJ
Mashl
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
John
J
Wallis
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.|Department of Genetics, Washington University, St. Louis, Missouri, USA.|Department of Mathematics, Washington University, St. Louis, Missouri, USA.
Michael C
MC
Wendl
Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri, USA.|Siteman Cancer Center, Washington University, St. Louis, Missouri, USA.|Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA.
Feng
F
Chen
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.|Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri, USA.|Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri, USA.|Siteman Cancer Center, Washington University, St. Louis, Missouri, USA.
Li
0000-0003-1517-2975
L
Ding
D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D062313:Databases, Pharmaceutical; D030562:Databases, Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins