Passenger Hotspot Mutations in Cancer

Cancer Cell. 2019 Sep 16;36(3):288-301.e14. doi: 10.1016/j.ccell.2019.08.002.

Abstract

Current statistical models for assessing hotspot significance do not properly account for variation in site-specific mutability, thereby yielding many false-positives. We thus (i) detail a Log-normal-Poisson (LNP) background model that accounts for this variability in a manner consistent with models of mutagenesis; (ii) use it to show that passenger hotspots arise from all common mutational processes; and (iii) apply it to a ∼10,000-patient cohort to nominate driver hotspots with far fewer false-positives compared with conventional methods. Overall, we show that many cancer hotspot mutations recurring at the same genomic site across multiple tumors are actually passenger events, recurring at inherently mutable genomic sites under no positive selection.

Keywords: Log-normal-Poisson; cancer; drivers; genomics; hotspots; mutability; mutations; passengers; selection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics*
  • DNA Mutational Analysis
  • Datasets as Topic
  • Genes, Tumor Suppressor
  • Genomics / methods*
  • Humans
  • Models, Genetic*
  • Mutagenesis*
  • Neoplasms / genetics*
  • Poisson Distribution
  • ROC Curve
  • Selection, Genetic
  • Whole Exome Sequencing