Evolving copy number gains promote tumor expansion and bolster mutational diversification

Zicheng Wang, Yunong Xia, Lauren Mills, Athanasios N. Nikolakopoulos, Nicole Maeser, Scott M. Dehm, Jason M. Sheltzer and Ruping Sun ()
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Zicheng Wang: University of Minnesota
Yunong Xia: University of Minnesota
Lauren Mills: University of Minnesota
Athanasios N. Nikolakopoulos: University of Minnesota
Nicole Maeser: University of Minnesota
Scott M. Dehm: University of Minnesota
Jason M. Sheltzer: Yale University
Ruping Sun: University of Minnesota

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The timing and fitness effect of somatic copy number alterations (SCNA) in cancer evolution remains poorly understood. Here we present a framework to determine the timing of a clonal SCNA that encompasses multiple gains. This involves calculating the proportion of time from its last gain to the onset of population expansion (lead time) as well as the proportion of time prior to its first gain (initiation time). Our method capitalizes on the observation that a genomic segment, while in a specific copy number (CN) state, accumulates point mutations proportionally to its CN. Analyzing 184 whole genome sequenced samples from 75 patients across five tumor types, we commonly observe late gains following early initiating events, occurring just before the clonal expansion relevant to the sampling. These include gains acquired after genome doubling in more than 60% of cases. Notably, mathematical modeling suggests that late clonal gains may contain final-expansion drivers. Lastly, SCNAs bolster mutational diversification between subpopulations, exacerbating the circle of proliferation and increasing heterogeneity.

Date: 2024
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DOI: 10.1038/s41467-024-46414-5

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