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

Matthew D. Wilkerson, Christopher R. Cabanski, Wei Sun, Katherine A. Hoadley, Vonn Walter, Lisle E. Mose, Melissa A. Troester, Peter S. Hammerman, Joel S. Parker, Charles M. Perou, D. Neil Hayes

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalNucleic acids research
Volume42
Issue number13
DOIs
StatePublished - Jan 1 2014

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RNA Sequence Analysis
Exome
DNA Sequence Analysis
Mutation
DNA
Neoplasms
Genome
RNA
Mutation Rate
Genomics
Lung Neoplasms
Cohort Studies
Breast Neoplasms
Technology

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Wilkerson, M. D., Cabanski, C. R., Sun, W., Hoadley, K. A., Walter, V., Mose, L. E., ... Hayes, D. N. (2014). Integrated RNA and DNA sequencing improves mutation detection in low purity tumors. Nucleic acids research, 42(13). https://doi.org/10.1093/nar/gku489
Wilkerson, Matthew D. ; Cabanski, Christopher R. ; Sun, Wei ; Hoadley, Katherine A. ; Walter, Vonn ; Mose, Lisle E. ; Troester, Melissa A. ; Hammerman, Peter S. ; Parker, Joel S. ; Perou, Charles M. ; Hayes, D. Neil. / Integrated RNA and DNA sequencing improves mutation detection in low purity tumors. In: Nucleic acids research. 2014 ; Vol. 42, No. 13.
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Wilkerson, MD, Cabanski, CR, Sun, W, Hoadley, KA, Walter, V, Mose, LE, Troester, MA, Hammerman, PS, Parker, JS, Perou, CM & Hayes, DN 2014, 'Integrated RNA and DNA sequencing improves mutation detection in low purity tumors', Nucleic acids research, vol. 42, no. 13. https://doi.org/10.1093/nar/gku489

Integrated RNA and DNA sequencing improves mutation detection in low purity tumors. / Wilkerson, Matthew D.; Cabanski, Christopher R.; Sun, Wei; Hoadley, Katherine A.; Walter, Vonn; Mose, Lisle E.; Troester, Melissa A.; Hammerman, Peter S.; Parker, Joel S.; Perou, Charles M.; Hayes, D. Neil.

In: Nucleic acids research, Vol. 42, No. 13, 01.01.2014.

Research output: Contribution to journalArticle

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AU - Cabanski, Christopher R.

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AU - Troester, Melissa A.

AU - Hammerman, Peter S.

AU - Parker, Joel S.

AU - Perou, Charles M.

AU - Hayes, D. Neil

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