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 studied the relationship of histogenesis and clonal diversification in GCTs by analysing the genome and transcriptome of 547 microdissected histological units. We found that the extensive diversification of tissues and genetic subclones were not correlated. However, we identified 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. Whilst this pattern was preserved across all GCTs, the developmental timing of the duplication varied between prepubertal and postpubertal cases. In addition, tumours of younger children exhibited distinct substitution signatures, including a novel one, 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, whilst identifying overarching tissue and tumour transcriptional and genomic features.