Neville, M. D. C. | bioRxiv Science

bioRxiv2022

Clonal diversification and histogenesis of malignant germ cell tumours

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.

cancer biology↗

bioRxiv2020

The mutational landscape of human somatic and germline cells

During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

genomics↗