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

Artem Lomakin, Jessica Svedlund, Carina Strell, Milana Gataric, Artem Shmatko, Gleb Rukhovich, Jun Sung Park, Young Seok Ju, Stefan Dentro, Vitalii Kleshchevnikov, Vasyl Vaskivskyi, Tong Li, Omer Ali Bayraktar, Sarah Pinder, Andrea L. Richardson, Sandro Santagata, Peter J. Campbell, Hege Russnes, Moritz Gerstung (), Mats Nilsson () and Lucy R. Yates ()
Additional contact information
Artem Lomakin: European Bioinformatics Institute (EMBL-EBI)
Jessica Svedlund: Stockholm University
Carina Strell: Stockholm University
Milana Gataric: European Bioinformatics Institute (EMBL-EBI)
Artem Shmatko: German Cancer Research Centre DKFZ
Gleb Rukhovich: Wellcome Sanger Institute
Jun Sung Park: European Bioinformatics Institute (EMBL-EBI)
Young Seok Ju: GSMSE, KAIST
Stefan Dentro: European Bioinformatics Institute (EMBL-EBI)
Vitalii Kleshchevnikov: Wellcome Sanger Institute
Vasyl Vaskivskyi: Wellcome Sanger Institute
Tong Li: Wellcome Sanger Institute
Omer Ali Bayraktar: Wellcome Sanger Institute
Sarah Pinder: Guys and St Thomas’ NHS Trust
Andrea L. Richardson: John Hopkins Medicine
Sandro Santagata: Harvard Medical School
Peter J. Campbell: Wellcome Sanger Institute
Hege Russnes: Oslo University Hospital
Moritz Gerstung: European Bioinformatics Institute (EMBL-EBI)
Mats Nilsson: Stockholm University
Lucy R. Yates: Wellcome Sanger Institute

Nature, 2022, vol. 611, issue 7936, 594-602

Abstract: Abstract Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1–3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. 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. 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. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. 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. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.

Date: 2022
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DOI: 10.1038/s41586-022-05425-2

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