Longitudinal structural variant phylogenies define tumor evolution under therapeutic selection pressure in metastatic prostate cancer

Abstract

Therapeutic pressure shapes tumor evolution by selecting for subclones with distinct genomic architectures. In metastatic castration-resistant prostate cancer (mCRPC), structural variants (SVs) are central to this process but rarely incorporated into clonal reconstruction from bulk DNA sequencing. We describe SVCFit, a computational framework that estimates the cellular fraction of diverse SV classes from whole-genome sequencing and uses these estimates to reconstruct clonal evolutionary relationships. SVCFit explicitly models SV-type-specific breakpoint and breakend patterns and accounts for local copy-number context, enabling accurate SV cellular-fraction estimation across heterogeneous tumor genomes. On simulated datasets and in silico mixtures of metastatic prostate cancer samples, SVCFit achieves lower estimation error than SVclone, the current state-of-the-art for bulk-sequencing SV cellular-fraction estimation. Applied to longitudinal whole-genome sequencing from patients with mCRPC treated with bipolar androgen therapy, SVCFit reveals marked treatment-associated clonal reconfiguration, including contraction of highly rearranged subclones and expansion of resistant populations defined by distinct structural alterations. By enabling reconstruction of SV-defined clonal architecture from routine whole-genome sequencing, SVCFit expands the toolkit for studying tumor evolution under therapy in precision oncology. The COMBAT trial that provided these samples is registered on ClinicalTrials.gov (NCT03554317; first posted 13 June 2018).