Journal
NATURE GENETICS
Volume 48, Issue 8, Pages 827-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3586
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Funding
- National Cancer Institute [R01CA180006, R01CA178383]
- National Human Genome Research Institute [U01HG006517]
- US Department of Defense [PC130118 (W81XWH-14-1-0458)]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01DK087960]
- Precision Medicine Pathway at the Washington University School of Medicine
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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.
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