Slide-DNA-seq spatially resolves genetic aberrations in intact tumor sections.

  • Major Finding: Slide-DNA-seq spatially resolves genetic aberrations in intact tumor sections.

  • Concept: Local tumor architecture is preserved, allowing the discovery of distinct clones and their copy-number alterations.

  • Impact: Use of this method can determine contribution of cell-intrinsic and -extrinsic factors to tumor progression.

Current deep or single-cell sequencing approaches can provide information on mutant allele frequency or phylogenetic lineages but not spatial organization, and current multiregion sequencing methods that preserve spatial context are not scalable. Building on the development of slide-RNA-seq, a method that detects spatially resolved genome-wide gene expression, Zhao, Chiang, and colleagues developed slide-DNA-seq, a method that allows spatially resolved DNA sequencing within intact tissue sections. Briefly, frozen tumor tissue sections are transferred onto an array of beads that are each indexed with a unique DNA barcode that corresponds to a spatial location. Histones are removed to allow unbiased DNA capture, and the barcodes transposed to create genomic fragments with adapter sequences. Each spatial barcode is then photocleaved from the beads, ligated to proximal genomic fragments, and PCR amplified to create a DNA library that can be sequenced by high-throughput paired-end sequencing to associate each genomic fragment with a spatial location. As proof of concept, slide-DNA-seq was used in mouse models to detect spatial distribution of copy-number alterations in distinct metastatic clones. In stage IIIB human primary colorectal tumor tissue sections, application of slide-DNA-seq to aggregates of tumor cells in tissue sections identified aggregates with similar copy-number alterations, supporting the hypothesis that each clone was derived from the same lineage. Several genetic aberrations were shared across all subclones, suggesting their occurrence early in tumor evolution, with other subclonal amplifications likely developing at a later timepoint, demonstrating that slide-DNA-seq can also be used to study evolution of clonal heterogeneity. Lastly, a multimodal approach in serial colorectal tumor sections using hematoxylin and eosin staining, slide-DNA-seq, and slide-RNA-seq to determine the relationship between cell-intrinsic features (i.e., subclonal identity), cell-extrinsic features (i.e., tumor density), and gene expression identified cell growth and proliferation–associated genes specific for subclonal identity and genes for cell adhesion molecules specific for tumor density. The use of spatial DNA sequencing may therefore complement spatial transcriptomics to allow high-resolution characterization of intratumoral heterogeneity within tumor tissue.

Zhao T, Chiang ZD, Morriss JW, LaFave LM, Murray EM, Del Priore I, et al. Spatial genomics enables multi-modal study of clonal heterogeneity in tissues. Nature 2022;601:85–91.

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