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Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.

Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3
Departments of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.
4
Department of Medicine, University of California, San Francisco, California, USA.
5
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
6
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California, USA.
7
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
8
Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
9
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
10
Weill Cornel Medical College, Cornell University, New York, New York, USA.
11
Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
12
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.

Abstract

Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized. An approach to detect significantly mutated residues, rather than methods that identify recurrently mutated genes, may uncover new biologically and therapeutically relevant driver mutations. Here, we developed a statistical algorithm to identify recurrently mutated residues in tumor samples. We applied the algorithm to 11,119 human tumors, spanning 41 cancer types, and identified 470 somatic substitution hotspots in 275 genes. We find that half of all human tumors possess one or more mutational hotspots with widespread lineage-, position- and mutant allele-specific differences, many of which are likely functional. In total, 243 hotspots were novel and appeared to affect a broad spectrum of molecular function, including hotspots at paralogous residues of Ras-related small GTPases RAC1 and RRAS2. Redefining hotspots at mutant amino acid resolution will help elucidate the allele-specific differences in their function and could have important therapeutic implications.

PMID:
26619011
PMCID:
PMC4744099
DOI:
10.1038/nbt.3391
[Indexed for MEDLINE]
Free PMC Article

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