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Nucleic Acids Res DOI:10.1093/nar/gku489

Integrated RNA and DNA sequencing improves mutation detection in low purity tumors.

Publication TypeJournal Article
Year of Publication2014
AuthorsWilkerson, MD, Cabanski, CR, Sun, W, Hoadley, KA, Walter, V, Mose, LE, Troester, MA, Hammerman, PS, Parker, JS, Perou, CM, D Hayes, N
JournalNucleic Acids Res
Date Published2014 Jul
KeywordsBreast Neoplasms, DNA Mutational Analysis, Female, Genes, Neoplasm, Humans, Lung Neoplasms, Mutation Rate, Neoplasms, Sequence Analysis, RNA

Identifying somatic mutations is critical for cancer genome characterization and for prioritizing patient treatment. DNA whole exome sequencing (DNA-WES) is currently the most popular technology; however, this yields low sensitivity in low purity tumors. RNA sequencing (RNA-seq) covers the expressed exome with depth proportional to expression. We hypothesized that integrating DNA-WES and RNA-seq would enable superior mutation detection versus DNA-WES alone. We developed a first-of-its-kind method, called UNCeqR, that detects somatic mutations by integrating patient-matched RNA-seq and DNA-WES. In simulation, the integrated DNA and RNA model outperformed the DNA-WES only model. Validation by patient-matched whole genome sequencing demonstrated superior performance of the integrated model over DNA-WES only models, including a published method and published mutation profiles. Genome-wide mutational analysis of breast and lung cancer cohorts (n = 871) revealed remarkable tumor genomics properties. Low purity tumors experienced the largest gains in mutation detection by integrating RNA-seq and DNA-WES. RNA provided greater mutation signal than DNA in expressed mutations. Compared to earlier studies on this cohort, UNCeqR increased mutation rates of driver and therapeutically targeted genes (e.g. PIK3CA, ERBB2 and FGFR2). In summary, integrating RNA-seq with DNA-WES increases mutation detection performance, especially for low purity tumors.


Alternate JournalNucleic Acids Res.
PubMed ID24970867
PubMed Central IDPMC4117748
Grant ListP30 ES010126 / ES / NIEHS NIH HHS / United States
U24 CA143848-02S1 / CA / NCI NIH HHS / United States
P50-CA058223 / CA / NCI NIH HHS / United States
P50 CA058223 / CA / NCI NIH HHS / United States
U24 CA143848 / CA / NCI NIH HHS / United States
F32CA142039 / CA / NCI NIH HHS / United States