Tracing the evolution of aneuploid cancers by multiregional sequencing with CRUST

Clonal deconvolution of mutational landscapes is crucial to understand the evolutionary dynamics of cancer. Two limiting factors for clonal deconvolution that have remained unresolved are variation in tumor cell fraction (TCF) and chromosomal copy number across different samples of the same tumor. We developed a semi-supervised algorithm that tracks variant calls through multi-sample spatiotemporal tumor data. While normalizing allele frequencies based on TCF it also adjusts for copy number changes at clonal deconvolution. Absent à priori copy number data, it renders in silico copy number estimations from bulk sequences. Using published and simulated tumor sequences, we reliably segregated clonal/subclonal variants even at low sequencing depth (∼50x). Given at least one pure tumor sample (>70% TCF), we could normalize and deconvolve paired samples down to a TCF of 40%. This renders a reliable clonal reconstruction well adapted to multi-regionally sampled solid tumor, which are often aneuploid and contaminated by non-cancer cells.