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.
Nature communications. 2024 Oct 26*** epublish ***
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, Clare Verrill, Testicular Cancer Genomics England Clinical Interpretation Partnership Consortium , Genomics England Research Consortium
Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. ., Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK., Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden., Genomics England, London, UK., Department of Biology, University of Konstanz, Universitaetsstrasse 10, D-78464, Konstanz, Germany., Manchester Cancer Research Centre, The University of Manchester, Manchester, UK., Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK., Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Department of Microbiology, Moyne Institute of Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland., Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK., Guy's and St Thomas' NHS Foundation Trust, London, UK., Department of Pathology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK., Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK., Weston Park Cancer Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK., Christie Hospital, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK., Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. ., Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. ., NIHR Oxford Biomedical Research Centre, Oxford, UK. .