Submitted by Livia Harriman on Tue, 05/11/2024 - 11:17
New insights into the genomic drivers of testicular cancer in adults have been discovered by detailed whole genome analysis of samples from the 100,000 Genomes Project.
Malignant germ cell tumours (GCTs) are complex cancers that affect patients of all ages. They develop from cells that produce eggs or sperm and mainly occur in the ovaries and testes.
Around 2,500 men are diagnosed with testicular germ cell tumours (TGCTs) every year in the UK.
The disease, although rare, is one of the most common cancers in adolescent and young adult men, with incidence rates rising globally in this group.
Fortunately, almost all men diagnosed with testicular cancer today are predicted to survive for at least ten years. Research will enable the development of better, targeted treatments to improve outcomes for patients with more aggressive forms of the disease.
Using tumour samples collected by the NHS for the Genomics England 100,000 Genomes Project, researchers have, for the first time, been able to use whole genome sequencing to study the causes of testicular germ cell tumours (TGCTs) in adults.
Researchers have mapped the changes to the genome of 60 tumour samples to understand what causes the different subtypes of TCGTs and how tumours evade detection by the body’s immune system. This could explain why the disease sometimes recurs.
The research team found that whole genome duplication, where the entire set of chromosomes within tumour cells are duplicated, is a very early event in TGCTs – possibly occurring in the developing foetus before birth – and plays a crucial role in cancer development. The team’s essential findings have been published in Nature Communications.
Professor Matthew Murray, Honorary Consultant Paediatric Oncologist at Addenbrooke’s Hospital, co-lead Paediatric Cancer Programme at the CRUK Cambridge Centre, University of Cambridge, and a senior author of the study, said: “Further studies will be required to understand the clinical significance of all the findings we discovered in this work.
“It’s taken an enormous amount of effort from all involved over the last nine years since the Testis Cancer Domain was formed to get us to this stage, so we are very pleased that this work can be shared with the scientific community.”
Prof Murray led the successful application for the Testis Cancer Genomic Interpretation Partnership (GeCIP) Domain to be included in Genomics England 100,000 Genomes Project in 2015 and is Co-Lead for the Testis Cancer Domain.
He added: “We are indebted to the participants who allowed their tumours to be sequenced as part of the 100,000 Genomes Project so that we can understand more about how these tumours arise.”
Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project
Professor Matthew Murray, University Professor and Honorary Consultant Paediatric Oncologist, working at both the Department of Pathology, Cambridge University and the Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, United Kingdom, is a senior and corresponding author on this critical study.
He led the successful application for the Testis Cancer Genomic Interpretation Partnership (GeCIP) Domain to be included in Genomics England 100,000 Genomes Project in 2015. He is the Co-Lead for the Testis Cancer Domain.
Professor Murray said: “This is an important work that uses whole genome sequencing to study testicular germ cell tumours (TGCTs) from adult patients. We found that whole genome duplication, or WGD, where the entire set of chromosomes within tumour cells are duplicated, is a very early event in TGCTs and plays a key role in cancer development. We also observed changes in some tumour cells linked to immune disruption and evasion which may, for example, be associated with increased risk of tumour recurrence”
He added: “Further studies will be required to understand the clinical significance of all the findings we discovered in this work. It’s taken enormous effort from all involved over the last nine years since the Testis Cancer Domain was formed to get us to this stage, so we are very pleased that this work can be shared with the scientific community. We are indebted to the participants who allowed their tumours to be sequenced as part of the 100,000 Genomes Project so that we can understand more about how these tumours arise”
Double Trouble: Whole Genome Duplication and Immune Disruption in Testicular Cancers
Testicular germ cell tumours (TGCT), while rare, are among the most common cancers in adolescent and young adult men, with incidence rates rising globally in this group1,2. Despite this, genomics research on TGCT has lagged behind that of other cancers, likely because the disease is typically treatable and has a low lifetime risk of mortality associated with testicular cancer. As a result, no major genomic sequencing initiatives have focused on collecting and analyzing data from TGCT patients—until recently.
The 100,000 Genomes Project, a landmark initiative conducted within the National Health Service (NHS) in England, is starting to fill this gap. By linking genomic data with longitudinal clinical information, this project provides a crucial resource for studying TGCTs at a genomic level. In our recent Nature Communications study, we aimed to dig deeper into the processes shaping testicular cancer genomes, from their origins in the womb to the mutational events that help these tumours evade the immune system. Ultimately, we aimed to uncover potential pathways for improved diagnosis and treatment strategies.
The journey behind this paper began in 2015 with the formation of the Testicular Cancer Genomics England Clinical Interpretation Partnership, which was driven by two key questions: What drives the diversity in TGCT subtypes, and how do genome alterations contribute to both their development and various modes of immune evasion? Given the prominence of TGCT and the clinical need to understand more aggressive forms of the disease, this investigation felt like a significant challenge. From the outset, we were curious about how genomic alterations might shape the progression of these tumours. We could explain the excellent prognosis and response of some subtypes of these tumours, even when metastatic.
Whole-genome duplication (WGD) is an event in which an organism's entire set of chromosomes is duplicated; this process can lead to accelerated tumour genome evolution, increased cancer heterogeneity, and poorer outcomes for patients3,4. Recent studies have found that genome doubling through whole genome duplication is a conspicuous and near-universal feature of TGCTs5,6. While WGD is shared across various cancers, it appears to play a particularly crucial role in shaping the TGCT genome, occurring very early in tumorigenesis—likely during fetal development. Our study focused on pinpointing the timing of WGD and other necessary genomic alterations, both about each other and chronologically, over the years or decades of a patient's life. Our findings revealed that specific mutational events were enriched, while others were suppressed following early WGD, tracing the evolutionary trajectory of these tumours. Understanding this sequence of genomic events will help us clarify precisely how TGCTs evolve from early cellular abnormalities to the development of malignant cells with the capacity to spread.
Interestingly, we also identified rare cases where characteristic gains of the short arm of chromosome 12 (12p gains) appeared to precede early WGD. In contrast, relatively late WGD events were observed in a few cases. What makes the discovery of these late WGD cases particularly surprising is that, in some cases, it shifts the earliest mutational events outside of the typical developmental window observed, raising a potential question about the presumed cell of origin in these cases. Could these be primordial germ cell (PGC)-like cells that persist into infancy, or might they point to an entirely different, previously undescribed cellular origin for TGCT tumorigenesis in such cases? There is still a considerable amount to learn about genome doubling in testicular cancer - the specific drivers of WGD during development, its prevalence in non-invasive precursor lesions, and how often such errors occur in germ cells without progressing to malignancy. Understanding these complexities in future studies will be crucial for advancing our knowledge of TGCT development and evolution.
One of the more surprising findings was the detection of loss of heterozygosity (LOH) of the HLA locus, a genomic alteration previously linked to immune evasion in other cancers7. Importantly, we found that HLA LOH was almost exclusively present in seminomas, the most common subtype of TGCT, prompting us to consider its potential link to variation in tumour-infiltrating lymphocytes (TILs). Although seminomas often display prominent TILs, some cases have notably fewer, and we still lack a clear understanding of what drives these differences or how they might affect long-term outcomes. Our findings suggest that HLA LOH might be one genomic mechanism enabling certain seminomas to evade immune detection, potentially contributing to lower TIL levels in these cases and opening future possibilities for targeted immunotherapies.
So, what comes next? While TGCT is considered a highly treatable cancer, understanding its genomic landscape opens up new possibilities for improving outcomes. Predicting the need for and response to treatment are attractive goals. While our study may be just the beginning, it lays the groundwork for a deeper understanding of TGCT and its genomic underpinnings, promising new avenues for targeted treatments for patients with more aggressive or refractory disease. We're optimistic that future studies, with larger and more clinically diverse cohorts in terms of presentation and outcomes, will allow us to build on our findings and uncover more about mutational processes in TGCT. Expanding this research to include rare and more aggressive TGCT subtypes will be vital to advancing our understanding of the disease. We're hopeful that this paper provides valuable insights into the diversity of genomic processes driving TGCT evolution and that these key findings can be translated in the future into real patient benefit. Ultimately, our study highlights the complexity of TGCT biology and the need for continued research into this rare and often overlooked cancer.
For those interested in this study's detailed findings and methodologies, the full paper is available here.
References:
- Le Cornet, C., et al. Testicular cancer incidence to rise by 25% by 2025 in Europe? Model-based predictions in 40 countries using population-based registry data. European Journal of Cancer 50, no. 4 (2014): 831-839.
- Huyghe, E., Plante, P., & Thonneau, P. F. Testicular cancer variations in time and space in Europe. European Urology 51, no. 3 (2007): 621-628.
- Bielski, C. M. et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nature Genetics 50 (2018):1189–1195.
- Dewhurst, S. M. et al. Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discovery 4, 175–185 (2014).
- Shen, H., et al. Integrated molecular characterization of testicular germ cell tumours. Cell Reports 23, no. 11 (2018): 3392-3406.
- Oliver, T. R., et al. Clonal diversification and histogenesis of malignant germ cell tumours. Nature Communications 13, no. 1 (2022): 4272
- McGranahan, N., et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171.6 (2017): 1259-1271.