![]() However, even the most exhaustive sampling strategy will struggle to provide an unbiased representation of the cancer clone territories, particularly across whole-tumour sections. Histology-driven sampling, such as laser capture microdissection (LCM) 21, combined with low-input nucleic acid library sequencing or even single-cell sequencing goes some way towards resolving subclone spatial structure 19. Lineage tracing using somatic mutations is a powerful tool for inferring the ancestral relationships between cancer subclones, but methods to perform this in preserved human tissue context are lacking 3, 14, 17, 18, 19, 20. Still, this information appears key because adverse cancer outcomes-growth, progression and recurrence-are properties of genetically distinct subclones 3, 12, 13, 14, 15, 16. Consequently, relatively little is currently known about the nature or causes of spatial patterns of cancer growth, phenotypic characteristics of distinct subclonal lineages or their interactions with tissue ecosystems 11. However, as genomic technologies typically assay DNA from dissociated tissues, the phenotypic consequences and the ecosystem pressures that are critical to fully understanding cancer evolution are lost 9, 10. ![]() Whole-genome sequencing (WGS) analysis of the average cancer detects thousands of somatic mutations and multiple genetically related yet distinct groups of cells termed ‘subclones’ 2, 7, 8. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.Ĭancers are complex and dynamic entities that are constantly reshaped by the interactions between neoplastic cells and their microenvironments 4, 5, 6. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. ![]() Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive 4, 5. Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour 1, 2, 3. ![]() Nature volume 611, pages 594–602 ( 2022) Cite this article Spatial genomics maps the structure, nature and evolution of cancer clones
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