Passenger Hotspot Mutations in Cancer
Menée à l'aide d'un modèle statistique et de données génomiques portant sur une cohorte d'environ 10 000 patients, cette étude démontre que de nombreuses mutations de "points chauds" de l'ADN tumoral sont en réalité passagères et surviennent de manière récurrente sans sélection positive sur des sites génomiques intrinsèquement mutables
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.