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

Máire Ní Leathlobhair (), Anna Frangou, Ben Kinnersley, Alex J. Cornish, Daniel Chubb, Eszter Lakatos, Prabhu Arumugam, Andreas J. Gruber, Philip Law, Avraam Tapinos, G. Maria Jakobsdottir, Iliana Peneva, Atef Sahli, Evie M. Smyth, Richard Y. Ball, Rushan Sylva, Ksenija Benes, Dan Stark, Robin J. Young, Alexander T. J. Lee, Vincent Wolverson, Richard S. Houlston, Alona Sosinsky, Andrew Protheroe, Matthew J. Murray (), David C. Wedge () and Clare Verrill ()
Additional contact information
Máire Ní Leathlobhair: University of Oxford
Anna Frangou: Max Planck Institute of Molecular Cell Biology and Genetics
Ben Kinnersley: The Institute of Cancer Research
Alex J. Cornish: The Institute of Cancer Research
Daniel Chubb: The Institute of Cancer Research
Eszter Lakatos: Chalmers University of Technology and University of Gothenburg
Prabhu Arumugam: Genomics England
Andreas J. Gruber: Universitaetsstrasse 10
Philip Law: The Institute of Cancer Research
Avraam Tapinos: The University of Manchester
G. Maria Jakobsdottir: Manchester Academic Health Science Centre
Iliana Peneva: University of Oxford
Atef Sahli: University of Oxford
Evie M. Smyth: Trinity College Dublin
Richard Y. Ball: Norfolk and Norwich University Hospitals NHS Foundation Trust
Rushan Sylva: Guy’s and St Thomas’ NHS Foundation Trust
Ksenija Benes: The Royal Wolverhampton NHS Trust
Dan Stark: University of Leeds
Robin J. Young: Sheffield Teaching Hospitals NHS Foundation Trust
Alexander T. J. Lee: Manchester Academic Health Science Centre
Vincent Wolverson: Genomics England
Richard S. Houlston: The Institute of Cancer Research
Alona Sosinsky: Genomics England
Andrew Protheroe: Oxford University Hospitals NHS Foundation Trust
Matthew J. Murray: Cambridge University Hospitals NHS Foundation Trust
David C. Wedge: University of Oxford
Clare Verrill: NIHR Oxford Biomedical Research Centre

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53193-6

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