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Clonal diversification and histogenesis of malignant germ cell tumours

Lookup NU author(s): Professor Rakesh Heer

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022, Crown. 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.

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Author(s): Oliver TRW, Chappell L, Sanghvi R, Deighton L, Ansari-Pour N, Dentro SC, Young MD, Coorens THH, Jung H, Butler T, Neville MDC, Leongamornlert D, Sanders MA, Hooks Y, Cagan A, Mitchell TJ, Cortes-Ciriano I, Warren AY, Wedge DC, Heer R, Coleman N, Murray MJ, Campbell PJ, Rahbari R, Behjati S

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2022

Volume: 13

Issue: 1

Online publication date: 11/08/2022

Acceptance date: 13/06/2022

Date deposited: 01/09/2022

ISSN (electronic): 2041-1723

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41467-022-31375-4

DOI: 10.1038/s41467-022-31375-4

PubMed id: 35953478

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