).jpg?sfvrsn=83bdab30_1)
The largest study to date of most common form of testicular cancer has uncovered a possible link between disease risk and variations in the genes controlling cell shape and movement.
By investigating the fundamental risk factors that may influence certain men inheriting testicular cancer, the study reveals new insights into how rare genetic variants may contribute to susceptibility – laying the groundwork for improved risk prediction and a better understanding of potential targets for future treatments.
The study, led by researchers at The Institute of Cancer Research, London, compared the genetic data of men with and without testicular germ cell tumours (TGCTs).
The tumours driving testicular cancer
TGCTs are tumours formed in germ cells, which are the cells that develop into sperm in the testes and eggs in the ovaries. They represent the most common form of testicular cancer, accounting for more than 90 per cent of cases.
This study, published in the journal European Urology Open Science, built on previous studies led by or involving scientists at The Institute of Cancer Research (ICR), analysed 1,435 TGCT cases and 18,284 cancer-free controls. The researchers used whole-exome sequencing – a technique for sequencing all the protein-coding regions of genes – to identify rare genetic variants that disrupt protein sequences and ultimately cause diseases, such as TGCTs.
The road to greater understanding
While previous genome-wide association (GWAS) studies have linked 78 fixed chromosome positions to TGCT risk – explaining more than 44 per cent of the disease’s heritability – much of the genetic basis remains unknown.
To uncover additional genetic factors, the research team aimed to evaluate rare and disruptive mutations using models that explain how certain inherited characteristics, such as eye colour or health problems, are passed down in families.
The study, which was primarily funded by the Movember Foundation and the ICR, which is both a research institute and a charity, pooled data from three TGCT case series, incorporating previous analyses conducted by the ICR and The Cancer Genome Atlas programme, as well as newly analysed cases from the UK Biobank. It also greatly benefitted from a newer and much larger dataset of cancer-free controls compared with prior studies, significantly improving its statistical prominence and reliability.
The importance of studying heritability in TGCT
This study reaffirms the understanding that TGCTs have a strong heritable basis (37–49 per cent), with immediate family members being four to six times more likely to develop the disease. While testicular cancer is highly treatable – with cure rates exceeding 95 per cent –better understanding how and why the disease runs in families could support earlier diagnosis and more targeted monitoring. Despite the team using the largest UK Biobank dataset to date, no individual genes were found to be significantly associated with TGCTs, highlighting the complexity of its genetic foundations and the need for continued research.
This study emphasises the challenge of pinpointing rare genetic variants in driving TGCTs. While past research has pointed to possible genes such as DNAAF1 and CHEK2 playing a role in TGCT susceptibility, these associations have not been consistently confirmed in larger studies.
The researchers did, however, through analysing groups of related genes, find that rare genetic variants potentially linked to TGCTs were found in genes associated with microtubular and ciliary pathways – the tiny structural and movement systems of cells that play a vital role in their function and development. These findings hint at multiple biological mechanisms that may contribute to TGCT development and warrant further investigation.
First author Zeid Kuzbari, a PhD student in the Translational Genomics Group at the ICR, said:
“While this study didn’t pinpoint a single causative gene, it has significantly advanced our understanding of TGCT genetics. The results suggest that testicular cancer risk is likely influenced by a complex interaction between multiple low-effect genetic variants rather than a single high-risk gene.
“From a patient perspective, these findings reinforce the importance of genetic research and analysis in the early detection and risk assessment of testicular cancer in those patients at higher risk. Although we have yet to identify a definitive genetic marker for TGCTs, studies like this pave the way for more personalised approaches to cancer prevention and treatment.”
A marathon, not a sprint
The lack of replication in larger studies emphasises a key barrier in genetic research, termed the ‘Winner’s curse’, where initial findings are often difficult to confirm in larger studies performed later. With ongoing advancements in next-generation sequencing and data-sharing initiatives, future studies will continue to refine our understanding of TGCT genetics, ultimately leading to improved risk prediction and targeted interventions for those at a higher genetic risk.
Senior author Professor Clare Turnbull, Professor of Translational Cancer Genetics in the Division of Genetics and Epidemiology and Group Leader of the Translational Genetics Group, said:
“We are continuing our research efforts and are currently in the process of a much larger analysis involving samples from 8,000 men with TGCTs. Larger datasets and novel analytical approaches are crucial in driving both our understanding and identification of the factors contributing to TGCT susceptibility to ultimately improve patient outcomes in the years ahead.”