Spatial genomics maps the structure, character and evolution of cancer clones

Subclonality is a universal feature of cancers yet how clones grow, are spatially organised, differ phenotypically or influence clinical outcome is unclear. To address this, we developed base specific in situ sequencing (BaSISS). In fixed tissues, transcripts harbouring clone-defining mutations are detected, converted into quantitative clone maps and characterised through multi-layered data integration. Applied to 8 samples from key stages of breast cancer progression BaSISS localised 1.42 million genotype informative transcripts across 4.9cm2 of tissue. Microscopic clonal topographies are shaped by resident tissue architectures. Distinct transcriptional, histological and immunological features distinguish coexistent genetic clones. Spatial lineage tracing temporally orders clone features associated with the emergence of aggressive clinical traits. These results highlight the pivotal role of spatial genomics in deciphering the mechanisms underlying cancer progression. ### Competing Interest Statement CS is co-owner of HistoOne AB, Sweden, and has research contracts with Prelude Dx, CA, US. MN is an advisor to 10X Genomics. JS is now (but was not at the time of contribution to this manuscript) an employee of Spatial Transcriptomics, Part of 10x Genomics, Inc, Sodra Fiskartorpsvagen 15C, 114 33 Stockholm, Sweden. Other authors declare no competing interests.