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 group^1,2. 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, there have been no major genomic sequencing initiatives specifically 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, our goal was 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 an important challenge to take on. From the outset, we were curious about how genomic alterations might shape the progression of these tumours, and 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 patients^3,4. As recent studies have found, genome doubling through whole genome duplication is a conspicuous and near-universal feature of TGCTs^5,6. While WGD is common 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. In our study, we focused on pinpointing the timing of WGD and other important genomic alterations, both relative to one another 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 to clarify precisely how TGCTs evolve from early cellular abnormalities to the development of malignant cells with the capacity to spread.

Interestingly, we identified rare cases where characteristic gains of the short arm of chromosome 12 (12p gains) appeared to precede early WGD, while in a small number of cases, relatively late WGD events were observed. 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 huge 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 levels of TILs 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 across the board. Predicting the need for and response to treatment are attractive goals, and 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 key 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 the detailed findings and methodologies of this study, the full paper is available here.

References:

1. 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.
2. Huyghe, E., Plante, P., & Thonneau, P. F. Testicular cancer variations in time and space in Europe. European Urology 51, no. 3 (2007): 621-628.
3. Bielski, C. M. et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nature Genetics 50 (2018):1189–1195.
4. Dewhurst, S. M. et al. Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discovery 4, 175–185 (2014).
5. Shen, H., et al. Integrated molecular characterization of testicular germ cell tumours. Cell Reports 23, no. 11 (2018): 3392-3406.
6. Oliver, T. R., et al. Clonal diversification and histogenesis of malignant germ cell tumours. Nature Communications 13, no. 1 (2022): 4272
7. McGranahan, N., et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171.6 (2017): 1259-1271.