Clonal diversification and histogenesis of malignant germ cell tumours

Thomas R. W. Oliver, Lia Chappell, Rashesh Sanghvi, Lauren Deighton, Naser Ansari-Pour, Stefan C. Dentro, Matthew D. Young, Tim H. H. Coorens, Hyunchul Jung, Tim Butler, Matthew D. C. Neville, Daniel Leongamornlert, Mathijs A. Sanders, Yvette Hooks, Alex Cagan, Thomas J. Mitchell, Isidro Cortes-Ciriano, Anne Y. Warren, David C. Wedge, Rakesh Heer, Nicholas Coleman, Matthew J. Murray, Peter J. Campbell, Raheleh Rahbari () and Sam Behjati ()
Additional contact information
Thomas R. W. Oliver: Wellcome Sanger Institute
Lia Chappell: Wellcome Sanger Institute
Rashesh Sanghvi: Wellcome Sanger Institute
Lauren Deighton: Wellcome Sanger Institute
Naser Ansari-Pour: University of Oxford
Stefan C. Dentro: Wellcome Sanger Institute
Matthew D. Young: Wellcome Sanger Institute
Tim H. H. Coorens: Wellcome Sanger Institute
Hyunchul Jung: Wellcome Sanger Institute
Tim Butler: Wellcome Sanger Institute
Matthew D. C. Neville: Wellcome Sanger Institute
Daniel Leongamornlert: Wellcome Sanger Institute
Mathijs A. Sanders: Wellcome Sanger Institute
Yvette Hooks: Wellcome Sanger Institute
Alex Cagan: Wellcome Sanger Institute
Thomas J. Mitchell: Wellcome Sanger Institute
Isidro Cortes-Ciriano: European Bioinformatics Institute (EMBL-EBI)
Anne Y. Warren: Cambridge University Hospitals NHS Foundation Trust
David C. Wedge: University of Oxford
Rakesh Heer: Newcastle University
Nicholas Coleman: Cambridge University Hospitals NHS Foundation Trust
Matthew J. Murray: Cambridge University Hospitals NHS Foundation Trust
Peter J. Campbell: Wellcome Sanger Institute
Raheleh Rahbari: Wellcome Sanger Institute
Sam Behjati: Wellcome Sanger Institute

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we study the relationship of histogenesis and clonal diversification in GCTs by analysing the genomes and transcriptomes of 547 microdissected histological units. We find no correlation between genomic and histological heterogeneity. However, we identify unifying features including the retention of fetal developmental transcripts across tissues, expression changes on chromosome 12p, and a conserved somatic evolutionary sequence of whole genome duplication followed by clonal diversification. While this pattern is preserved across all GCTs, the developmental timing of the duplication varies between prepubertal and postpubertal cases. In addition, tumours of younger children exhibit distinct substitution signatures which may lend themselves as potential biomarkers for risk stratification. Our findings portray the extensive diversification of GCT tissues and genetic subclones as randomly distributed, while identifying overarching transcriptional and genomic features.

Date: 2022
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DOI: 10.1038/s41467-022-31375-4

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