Passenger Hotspot Mutations in Cancer

Julian M Hess; Andre Bernards; Jaegil Kim; Mendy Miller; Amaro Taylor-Weiner; Nicholas J Haradhvala; Michael S Lawrence; Gad Getz

doi:10.1016/j.ccell.2019.08.002

Passenger Hotspot Mutations in Cancer

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

Authors

Julian M Hess¹, Andre Bernards², Jaegil Kim¹, Mendy Miller¹, Amaro Taylor-Weiner¹, Nicholas J Haradhvala³, Michael S Lawrence⁴, Gad Getz⁵

Affiliations

¹ The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA.
³ The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ 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: mslawrence@mgh.harvard.edu.
⁵ 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: gadgetz@broadinstitute.org.

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
Exome Sequencing
Genes, Tumor Suppressor
Genomics / methods*
Humans
Models, Genetic*
Mutagenesis*
Neoplasms / genetics*
Poisson Distribution
ROC Curve
Selection, Genetic

Abstract

Publication types

MeSH terms

Grants and funding