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

Testicular Cancer Genomics England Clinical Interpretation Partnership Consortium; Genomics England Research Consortium; 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

doi:10.1038/s41467-024-53193-6

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

Testicular Cancer Genomics England Clinical Interpretation Partnership Consortium, Genomics England Research Consortium, 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 StarkRobin J Young, Alexander T J Lee, Vincent Wolverson, Richard S Houlston, Alona Sosinsky, Andrew Protheroe, Matthew J Murray, David C Wedge, Clare Verrill

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	9247
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-53193-6
Publication status	Published - 26 Oct 2024

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-53193-6Licence: CC BY

NIHR Manchester Biomedical Research Centre
Bruce, I. (PI), Lord, G. (CoI), Lennon, R. (CoI), Black, G. (CoI), Wedge, D. (CoI), Morris, A. (CoI), Hussell, T. (CoI), Sharrocks, A. (CoI), Stivaros, S. (CoI), Buch, M. (CoI), Gough, J. (CoI), Kostarelos, K. (CoI), Thistlethwaite, F. (CoI), Kadler, K. (CoI), Barton, A. (CoI), Hyrich, K. (CoI), Mcbeth, J. (CoI), O'Neill, T. (CoI), Vestbo, J. (CoI), Simpson, A. (CoI), Singh, S. (CoI), Smith, J. (CoI), Felton, T. (CoI), Murray, C. (CoI), Griffiths, C. (CoI), Cullum, N. (CoI), Rhodes, L. (CoI), Warren, R. (CoI), Paus, R. (CoI), Dumville, J. (CoI), Viros Usandizaga, A. (CoI), Keavney, B. (CoI), Tomaszewski, M. (CoI), Allan, S. (CoI), Body, R. (CoI), Cartwright, E. (CoI), Heagerty, A. (CoI), Kalra, P. (CoI), Miller, C. (CoI), Rutter, M. (CoI), Smith, C. (CoI), Trafford, A. (CoI), Evans, D. (CoI), Crosbie, E. (CoI), Crosbie, P. (CoI), Harvie, M. (CoI), Howell, S. (CoI), Renehan, A. (CoI), Dive, C. (CoI), Blackhall, F. (CoI), Landers, D. (CoI), Krebs, M. (CoI), Cook, N. (CoI), Clarke, R. (CoI), Taylor, S. (CoI), Jorgensen, C. (CoI), Lorigan, P. (CoI), Jayson, G. (CoI), Valle, J. (CoI), Mccabe, M. (CoI), Armstrong, A. (CoI), Freitas, A. (CoI), Illidge, T. (CoI), Choudhury, A. (CoI), Hoskin, P. (CoI), West, C. (CoI), Van Herk, M. (CoI), Faivre-Finn, C. (CoI), Bristow, R. (CoI), Kirkby, K. (CoI), Birtle, A. (CoI), Mackay, R. (CoI), Radford, J. (CoI), Linton, K. (CoI), Higham, C. (CoI), Munro, K. (CoI), Plack, C. (CoI), Arden Armitage, C. (CoI), Bruce, I. (CoI), Moore, D. (CoI), Saunders, G. (CoI), Stone, M. (CoI), Haddock, G. (CoI), Lewis, S. (CoI), Elliott, R. (CoI), Green, J. (CoI), Lovell, K. (CoI), Morrison, A. (CoI), Shaw, J. (CoI), Bucci, S. (CoI), Ainsworth, J. (CoI), Webb, R. (CoI), Newman, W. (CoI), Banka, S. (CoI), Clayton-Smith, J. (CoI), Payne, K. (CoI), Moldovan, R. (CoI), Wynn, R. (CoI) & Jones, S. (CoI)
1/12/22 → 30/11/27
Project: Research

Cite this

Testicular Cancer Genomics England Clinical Interpretation Partnership Consortium, Genomics England Research Consortium, Ní Leathlobhair, M., Frangou, A., Kinnersley, B., Cornish, A. J., Chubb, D., Lakatos, E., Arumugam, P., Gruber, A. J., Law, P., Tapinos, A., Jakobsdottir, G. M., Peneva, I., Sahli, A., Smyth, E. M., Ball, R. Y., Sylva, R., Benes, K., ... Verrill, C. (2024). Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project. Nature Communications, 15(1), Article 9247. https://doi.org/10.1038/s41467-024-53193-6

@article{8e36aa4693c24b4aa44c4e8af55488c5,

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

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.",

keywords = "Humans, Testicular Neoplasms/genetics, Male, Neoplasms, Germ Cell and Embryonal/genetics, Adult, DNA Copy Number Variations/genetics, Seminoma/genetics, Genomics/methods, Whole Genome Sequencing, Genome, Human, Mutation",

author = "{Testicular Cancer Genomics England Clinical Interpretation Partnership Consortium} and {Genomics England Research Consortium} and {N{\'i} Leathlobhair}, M{\'a}ire and Anna Frangou and Ben Kinnersley and Cornish, {Alex J} and Daniel Chubb and Eszter Lakatos and Prabhu Arumugam and Gruber, {Andreas J} and Philip Law and Avraam Tapinos and Jakobsdottir, {G Maria} and Iliana Peneva and Atef Sahli and Smyth, {Evie M} and Ball, {Richard Y} and Rushan Sylva and Ksenija Benes and Dan Stark and Young, {Robin J} and Lee, {Alexander T J} and Vincent Wolverson and Houlston, {Richard S} and Alona Sosinsky and Andrew Protheroe and Murray, {Matthew J} and Wedge, {David C} and Clare Verrill",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = oct,

day = "26",

doi = "10.1038/s41467-024-53193-6",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Testicular Cancer Genomics England Clinical Interpretation Partnership Consortium, Genomics England Research Consortium, Ní Leathlobhair, M, Frangou, A, Kinnersley, B, Cornish, AJ, Chubb, D, Lakatos, E, Arumugam, P, Gruber, AJ, Law, P, Tapinos, A, Jakobsdottir, GM, Peneva, I, Sahli, A, Smyth, EM, Ball, RY, Sylva, R, Benes, K, Stark, D, Young, RJ, Lee, ATJ, Wolverson, V, Houlston, RS, Sosinsky, A, Protheroe, A, Murray, MJ, Wedge, DC & Verrill, C 2024, 'Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project', Nature Communications, vol. 15, no. 1, 9247. https://doi.org/10.1038/s41467-024-53193-6

Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project. / Testicular Cancer Genomics England Clinical Interpretation Partnership Consortium; Genomics England Research Consortium; Ní Leathlobhair, Máire et al.
In: Nature Communications, Vol. 15, No. 1, 9247, 26.10.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project

AU - Testicular Cancer Genomics England Clinical Interpretation Partnership Consortium

AU - Genomics England Research Consortium

AU - Ní Leathlobhair, Máire

AU - Frangou, Anna

AU - Kinnersley, Ben

AU - Cornish, Alex J

AU - Chubb, Daniel

AU - Lakatos, Eszter

AU - Arumugam, Prabhu

AU - Gruber, Andreas J

AU - Law, Philip

AU - Tapinos, Avraam

AU - Jakobsdottir, G Maria

AU - Peneva, Iliana

AU - Sahli, Atef

AU - Smyth, Evie M

AU - Ball, Richard Y

AU - Sylva, Rushan

AU - Benes, Ksenija

AU - Stark, Dan

AU - Young, Robin J

AU - Lee, Alexander T J

AU - Wolverson, Vincent

AU - Houlston, Richard S

AU - Sosinsky, Alona

AU - Protheroe, Andrew

AU - Murray, Matthew J

AU - Wedge, David C

AU - Verrill, Clare

PY - 2024/10/26

Y1 - 2024/10/26

N2 - 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.

AB - 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.

KW - Humans

KW - Testicular Neoplasms/genetics

KW - Male

KW - Neoplasms, Germ Cell and Embryonal/genetics

KW - Adult

KW - DNA Copy Number Variations/genetics

KW - Seminoma/genetics

KW - Genomics/methods

KW - Whole Genome Sequencing

KW - Genome, Human

KW - Mutation

U2 - 10.1038/s41467-024-53193-6

DO - 10.1038/s41467-024-53193-6

M3 - Article

C2 - 39461959

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 9247

ER -

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

Abstract

Keywords

UN SDGs

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NIHR Manchester Biomedical Research Centre

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