Inferring tumor absolute copy number and clonal substructure from single-cell chromatin accessibility

Accurate inference of absolute copy numbers beyond simple gains and losses from single-cell chromatin accessibility (scATAC-seq) data remains challenging, thereby obscuring the distinction between genetic and epigenetically driven oncogenic dependencies. Here, we present TeaCNV, a computational framework that reconstructs clonal absolute copy number profiles and tumor clonal architectures from scATAC-seq data without matched DNA baselines. Through validation both in silico and against bulk whole-genome sequencing in renal cell carcinomas, TeaCNV resolved subclonal absolute copy number profiles with less than 10% error and detected copy number variations (CNVs) with 98.6% accuracy, outperforming existing methods. Applied to six cancer types including renal, breast, pancreatic, head and neck, colorectal, and ovarian cancers, TeaCNV delineated polyclonal architectures and revealed distinct chromatin accessibility patterns driven by CNVs in key driver genes, including AKT2, ZNF217, and SOX2. By enabling absolute copy number profiling and clonal deconvolution from epigenomic assays, TeaCNV bridges critical gaps in studying oncogenic dependencies and genotype-phenotype relationships at single-cell resolution.