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 Coorens, Hyunchul Jung, Timothy Butler, Matthew D. C. Neville, Daniel Leongamornlert, Mathijs A. Sanders, Yvette Hooks, Alex Cagan, Thomas J. Mitchell, Isidro Cortés‐Ciriano, Anne Y. Warren, David C. Wedge, Rakesh Heer, Nicholas Coleman, Matthew J. Murray, Peter J. Campbell, Raheleh Rahbari, Sam Behjati
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.