Principles of subclonal gene dosage across human cancer

Abstract Intratumor heterogeneity drives disease progression, but even though subclonal copy number variation (CNV) is a major contributor to this heterogeneity 1 , its impact on cell phenotype is not fully understood. Here, by applying high-quality joint whole genome sequencing and mRNA profiling in single cells (DNTR-seq 2 ) to solid tumors and leukemias from 57 patients, we have analyzed the in vivo transcriptional effect of subclonal CNVs within a tumor. We found that gene dosage is generally additive in low and moderate copy states, but that cancer-type-specific compensation is common, and core promoter elements are associated with reduced additivity. We find that different classes of subclonal CNV impose varying degrees of transcriptional constraints on a cell, with highly amplified megabase-size regions associated with a strong effect both in cis and trans , while arm level CNVs generally exert a milder effect. We also describe a previously unappreciated class of tumors with transient clonality , where every cell is genetically highly distinct. We find that transient clonality is common in ovarian cancer and soft tissue sarcoma, that it is preceded by a whole genome duplication event, and that gene dosage in these tumors affects transcript abundance to a similar degree as in cancer with stable subclones.