Cancer Cell 2019 Sep;36(3):288-301.e14
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:
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.