Journal Article

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

Lakatos, Eszter, Frangou, Anna, Gruber, Andreas J., Jakobsdottir, G. Maria, Verrill, Clare, Ball, Richard Y., Protheroe, Andrew, Ní Leathlobhair, Máire, Stark, Dan, Chubb, Daniel, Sosinsky, Alona, Tapinos, Avraam, Wedge, David C., Cornish, Alex J., Houlston, Richard S., Smyth, Evie M., Young, Robin J., Kinnersley, Ben, Law, Philip, Benes, Ksenija, Lee, Alexander T. J., Sylva, Rushan, Arumugam, Prabhu, Peneva, Iliana, Murray, Matthew J., Sahli, Atef, Wolverson, Vincent

2024

Overview

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. Testicular germ cell tumours (TGCT) are the most common cancers in young men. Here, the authors analyse the genomic landscape of TGCT using data from the Genomics England 100,000 Genomes Project, revealing divergent evolutionary trajectories and the prevalence of human leukocyte antigen loss.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 631/114 / 631/67/1836 / 631/67/580 / 631/67/68 / 631/67/69 / Adult / Antigens / Cancer / Copy number / Data analysis / Divergence / DNA Copy Number Variations - genetics / Gene sequencing / Genome, Human / Genomes / Genomic analysis / Genomics / Genomics - methods / Histocompatibility antigen HLA / Humanities and Social Sciences / Humans / Leukocytes / Male / Medical Genetics and Genomics / Medicinsk genetik och genomik / multidisciplinary / Mutation / Neoplasms, Germ Cell and Embryonal - genetics / Neoplasms, Germ Cell and Embryonal - pathology / Pathogenesis / Science / Science (multidisciplinary) / Seminoma / Seminoma - genetics / Seminoma - pathology / Subgroups / Testes / Testicular Neoplasms - genetics / Testicular Neoplasms - pathology / Tumors / Whole Genome Sequencing