Evaluating the evaluation of cancer driver genes

Collin J. Tokheim, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Rachel Karchin

Research output: Contribution to journalArticle

Abstract

Sequencing has identified millions of somatic mutations in human cancers, but distinguishing cancer driver genes remains a major challenge. Numerous methods have been developed to identify driver genes, but evaluation of the performance of these methods is hindered by the lack of a gold standard, that is, bona fide driver gene mutations. Here, we establish an evaluation framework that can be applied to driver gene prediction methods. We used this framework to compare the performance of eight such methods. One of these methods, described here, incorporated a machinelearning- based ratiometric approach. We show that the driver genes predicted by each of the eight methods vary widely. Moreover, the P values reported by several of the methods were inconsistent with the uniform values expected, thus calling into question the assumptions that were used to generate them. Finally, we evaluated the potential effects of unexplained variability in mutation rates on false-positive driver gene predictions. Our analysis points to the strengths and weaknesses of each of the currently available methods and offers guidance for improving them in the future.

Original languageEnglish (US)
Pages (from-to)14330-14335
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number50
DOIs
StatePublished - Dec 13 2016

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Keywords

  • Cancer genomics
  • Cancer mutations
  • Computational method evaluation
  • DNA sequencing
  • Driver genes

ASJC Scopus subject areas

  • General

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