New genetic changes linked to testicular cancer offer fresh insights into the disease and its treatment

Testicular cancer, though accounting for only about 1% of all cancers in men, is the most common cancer among those aged 15 to 44. Each year, nearly 200 men in Ireland are diagnosed with this cancer and incidence rates have risen in recent years -- a trend also observed in Northern and Central Europe.

Fortunately, testicular cancer is highly treatable, especially when detected early, with survival rates exceeding 90%. However, patients with the highest-risk disease face a significantly lower prognosis, with only around a 50% chance of survival despite extensive clinical trials, and existing chemotherapy treatments carry significant toxicities and associated side effects.

Using data from the 100,000 Genomes Project, led by Genomics England and NHS England, the scientists applied whole genome sequencing (WGS) to 60 patient samples to address key unresolved biological and clinical questions in testicular germ cell tumours (TGCTs). Their work has just been published in leading international journal Nature Communications.

Among the key findings are:

1. New potential cancer drivers in testicular cancer, including drivers specific to certain subtypes, which may help stratify patients based on their tumour characteristics
2. A reconstruction of evolutionary trajectories of genome alterations and probable progression pathways in TGCT
3. Discovery of a broader range of mutational signatures associated with TGCT. These are distinctive patterns of DNA damage, which can reflect various carcinogenic exposures (e.g. smoking, UV light) and enable a retrospective look at exposure-related cancer risk
4. Previously unidentified recurrent mutational hotspots in testicular cancer
5. Identification of a genomic immune mechanism unique to TGCT, predominantly in seminomas, the most common tumour subtype.

First author of the research, Máire Ní Leathlobhair, Assistant Professor in Trinity College Dublin's School of Genetics and Microbiology, said: "We have taken a major leap forward in our understanding of how this disease develops and gained important insights into potential treatment strategies, which is of course key as we seek better patient outcomes.

"Importantly, this research was only possible thanks to the valuable contribution of tissue samples from participants in the 100,000 Genomes Project and the collaborative efforts of medical professionals in the NHS. It represents one of the first relatively large-scale testicular cancer landscape studies using a powerful whole genome sequencing approach, which was key in revealing the new insights that other techniques would not have captured.

"This research aimed to transform genomic insights into meaningful patient outcomes, bridging fundamental discoveries with translational applications, and it also serves as a good example of how large volumes of patient data and samples can provide us with a more detailed view of a disease."

This study was a collaborative effort led by senior authors Profs. Matthew Murray, Andrew Protheroe, Clare Verrill, and David Wedge and involved a dedicated team of researchers, clinicians, and trainees from both academia and the NHS, with contributions from Trinity, the University of Oxford, the University of Cambridge, and the University of Manchester.

To further enhance understanding of the disease, the researchers now hope to involve more participants to include a wider diversity of outcomes, ethnicities, and types of testicular cancers.