Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity
By Matthew T. Chang, S. Asthana, S. Gao, Byron H. Lee, J. Chapman, Cyriac Kandoth, Jianjiong Gao, Nicholas D. Socci, D. Solit, Adam B. Olshen and 2 more. Nature Biotechnology, 2015
739 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/7c7e61d62f3ea9226992eca71b726bcc231ed113
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Citations in the corpus
- The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers (2018, methodology): “Recurrent hotspot mutations were identified as previously described (Chakravarty et al., 2017; Chang et al., 2016).”
- Clinical sequencing defines the genomic landscape of metastatic colorectal cancer (2018, background): “…2013 RRID:SCR_010779; http://archive.broadinstitute.org/ cancer/cga/mutsig Other cBioPortal Memorial Sloan Kettering Cancer Center, New York, NY RRID:SCR_014555 http://www.cbioportal.org/ Cancer Hotspots Chang et al., 2016 http://cancerhotspots.org OncoKB Chakravarty et al., 2017 http://oncokb.org”
- Genomic correlates of clinical outcome in advanced prostate cancer (2019, methodology): “2B, enrichment analysis using a binomial distribution test was performed as previously described (45) to identify genes that had a significant fraction of known or likely oncogenic alterations (as defined by OncoKB) among all identified SNVs.”
- Recon3D: A Resource Enabling A Three-Dimensional View of Gene Variation in Human Metabolism (2018, neutral): “Furthermore, we obtained detailed annotations about each of the mutations from cBioportal 37 , including whether a gene is a known oncogene 37,38 (KO) or the mutation is recurrent 12 , has gain-of-function (GOF), and has a drug association.”
- The long tail of oncogenic drivers in prostate cancer (2018, neutral): “Any mutations in hotspot genes, defined by cancerhotspots.org 34 , initially called by MuTect but subsequently filtered out were rescued for the final variant list.”