Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project.

Testicular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression.

Keywords

Humans, Testicular Neoplasms, Male, Neoplasms, Germ Cell and Embryonal, Adult, DNA Copy Number Variations, Seminoma, Genomics, Whole Genome Sequencing, Genome, Human, Mutation

Journal Title

Nat Commun

Journal ISSN

2041-1723
2041-1723

Publisher

Springer Nature

Publisher DOI

https://doi.org/10.1038/s41467-024-53193-6

Rights and licensing

Except where otherwised noted, this item's license is described as Attribution 4.0 International

Sponsorship

We thank the participants for contributing to this study. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (GEL; a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research (NIHR) and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by participants and collected by the National Health Service as part of their care and support. This work was co-funded by the NIHR Manchester Biomedical Research Centre (NIHR203308). C.V. is partly funded by the NIHR Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. A.J.C., D.C., B.K., and R.S.H. were supported by funding from the Wellcome Trust (214388) and Cancer Research UK (C1298/A8362). The authors would like to acknowledge Dr Sam Behjati and Thomas Oliver of the Wellcome Sanger Institute for interesting discussions and Peter O’Donovan for technical support.

Collections

University of Cambridge Research Outputs (Articles and Conferences)