Testicular cancer in families is usually caused by the accumulation of minor genetic changes that have only a small effect on their own, but together can add up to a significant risk.
A new study led by scientists at The Institute of Cancer Research, London shows that a mixed set of common, single-letter changes to the DNA code, each of which slightly increase a man’s risk of testicular cancer, play the biggest role in causing the disease.
Some 49 single-letter of these single-letter alterations, called single nucleotide polymorphisms, have been linked to testicular cancer so far, almost all by an international collaboration led by the ICR and largely funded by The Movember Foundation.
All men inherit a mixture of these variations from their parents.
To make their discovery, published in European Urology, the researchers made an in-depth comparison between DNA from around 4,000 men with testicular germ cell tumour (TGCT) and 12,000 men who did not develop it.
TGCT is by far the most common form of testicular cancer, and the most common cancer in young men.
Long-standing question resolved
The new study, funded by The Movember Foundation and the ICR, presents the answer to an important long-standing question about the causes of testicular cancer that runs in families, passed on through the generations.
Until now, scientists did not know which of three possible explanations accounted for the cause of familial cancer.
Was it many minor genetic factors added together? Previous studies have already confirmed that this is why most cases of ‘sporadic’ testicular cancer emerge in men with no family history of the disease.
Or was it something to do with lifestyle – experiences shared by family members that increased risk?
Or was it some rare major genetic mutation that led to an increase in risk, but was so far undiscovered by scientists? These ‘high-penetrance’ mutations are well-known in other cancers, like BRCA mutations in breast cancer, but none had been found so far in testicular cancer.
The new study answers the question, showing that the large majority of cases of TGCT are down to many minor genetic factors.
Some 84-100 per cent of cases are caused by a combination of this mixed set of variations, the research shows.
Discovery could help inform future screenings
“Our study uncovers the genetic basis for familial cases of the most common type of testicular cancer, and represents an important step forward in our understanding of the disease.
“While not ruling out the influence of other factors, it shows that the majority of cases are linked to the inheritance of a set of minor genetic alterations that together can add up to a sharp increase in risk.
“In the short term, our discovery will help in counselling men who might be worried about their risk of developing testicular cancer. In the longer term, it could help inform future screening programmes for testicular cancer that might diagnose it earlier.”