title: RADIA: RNA and DNA integrated analysis for somatic mutation detection.
abstract: The detection of somatic single nucleotide variants is a crucial component to the characterization of the cancer genome. Mutation calling algorithms thus far have focused on comparing the normal and tumor genomes from the same individual. In recent years, it has become routine for projects like The Cancer Genome Atlas (TCGA) to also sequence the tumor RNA. Here we present RADIA (RNA and DNA Integrated Analysis), a novel computational method combining the patient-matched normal and tumor DNA with the tumor RNA to detect somatic mutations. The inclusion of the RNA increases the power to detect somatic mutations, especially at low DNA allelic frequencies. By integrating an individual's DNA and RNA, we are able to detect mutations that would otherwise be missed by traditional algorithms that examine only the DNA. We demonstrate high sensitivity (84%) and very high precision (98% and 99%) for RADIA in patient data from endometrial carcinoma and lung adenocarcinoma from TCGA. Mutations with both high DNA and RNA read support have the highest validation rate of over 99%. We also introduce a simulation package that spikes in artificial mutations to patient data, rather than simulating sequencing data from a reference genome. We evaluate sensitivity on the simulation data and demonstrate our ability to rescue back mutations at low DNA allelic frequencies by including the RNA. Finally, we highlight mutations in important cancer genes that were rescued due to the incorporation of the RNA.
authors.affiliation: University of California Santa Cruz Genomics Institute, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Amie J
authors.initials: AJ
authors.lastname: Radenbaugh
authors.affiliation: University of California Santa Cruz Genomics Institute, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Singer
authors.initials: S
authors.lastname: Ma
authors.affiliation: University of California Santa Cruz Genomics Institute, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Ewing
authors.affiliation: University of California Santa Cruz Genomics Institute, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stuart
authors.affiliation: Division of Hematology/Oncology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.affiliation: University of California Santa Cruz Genomics Institute, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: University of California Santa Cruz Genomics Institute, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Haussler
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods*; D017423:Sequence Analysis, RNA / Q000379:methods*; D012984:Software