Joint analysis of single‐cell and bulk tissue sequencing data to infer intratumor heterogeneity

Abstract Many computational methods have been developed to discern intratumor heterogeneity (ITH) using DNA sequence data from bulk tumor samples. These methods share an assumption that two mutations arise from the same subclone if they have similar mutant allele‐frequencies (MAFs), and thus it is difficult or impossible to distinguish two subclones with similar MAFs. Single‐cell DNA sequencing (scDNA‐seq) data can be very informative for ITH inference. However, due to the difficulty of DNA amplification, scDNA‐seq data are often very noisy. A promising new study design is to collect both bulk and single‐cell DNA‐seq data and jointly analyze them to mitigate the limitations of each data type. To address the analytic challenges of this new study design, we propose a computational method named BaSiC ( B ulk tumor a nd Si ngle C ell), to discern ITH by jointly analyzing DNA‐seq data from bulk tumor and single cells. We demonstrate that BaSiC has comparable or better performance than the methods using either data type. We further evaluate BaSiC using bulk tumor and single‐cell DNA‐seq data from a breast cancer patient and several leukemia patients.