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

• Published in: Nature biotechnology Vol. 34; no. 2; pp. 155 - 163
• Main Authors: Chang, Matthew T, Asthana, Saurabh, Gao, Sizhi Paul, Lee, Byron H, Chapman, Jocelyn S, Kandoth, Cyriac, Gao, JianJiong, Socci, Nicholas D, Solit, David B, Olshen, Adam B, Schultz, Nikolaus, Taylor, Barry S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2016; Nature Publishing Group
• Subjects: 45/23; 631/114/2164; 631/61/212/2166; 631/67/69; 692/308/2056; Agriculture; Algorithms; Amino acids; analysis; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cancer; Computational Biology; DNA Mutational Analysis - methods; Gene mutations; Genetic aspects; Guanosine triphosphatase; Health aspects; Humans; Life Sciences; Mutation; Mutation - genetics; Neoplasms - genetics; Observations; Residues; Tumors
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt.3391

Detection of recurrently mutated nucleotides identifies novel cancer hotspots in an analysis of >11,000 human tumor samples. 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.