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Researchers develop new genetic tool to detect risk of multi-cancer syndrome

An international collaboration led by scientists from QIMR Berghofer and Peter MacCallum Cancer Centre has developed a new assessment tool for better identifying people most at risk of developing the devastating genetic multi-cancer disease, Li-Fraumeni syndrome.

People with Li-Fraumeni syndrome develop multiple cancers at a young age, including breast cancers, brain tumours, sarcomas, adrenal gland cancers, and leukaemia. They are also more prone to very rare cancers.

The only recognised cause of Li-Fraumeni syndrome is inherited changes in the gene called TP53 in every cell of the body. The TP53 gene, which is often called ‘the guardian of the genome’, is responsible for tracking the proper division of cells and thereby preventing tumours from developing.

TP53 works like a brake in a car. While there is some risk of an accident when driving, safety devices such as brakes make crashes less likely. If the brake is broken, the driver is at a much higher risk of crashing. Certain changes in TP53 in the cells of the body put people at a much higher risk of cancers.

The lead researcher from QIMR Berghofer’s Molecular Cancer Epidemiology Group, Dr Cristina Fortuno, said thousands of possible genetic variations in the TP53 gene have been identified in the past, but not all of them will cause Li-Fraumeni syndrome.

“Our assessment tool brings together information from many areas to more accurately pinpoint which variants in the TP53 gene cause the syndrome. Of the more than 1000 variants that we examined, we identified 500 as likely to cause this disease,” Dr Fortuno said.

“The tool improves on previous genetic approaches by incorporating a wider range of information, including personal and family history of cancer, variant frequency in the general population, and breast tumour pathology.”

The head of the Familial Cancer Research group at the Peter MacCallum Cancer Centre and joint-senior study author, Professor Paul James, said this is the most comprehensive statistically derived genetic prediction tool to date for the disease.

“Li-Fraumeni syndrome was thought to be a rare genetic condition, affecting about one in 5000 people, but advances in genetic sequencing are identifying more and more people carrying TP53 genetic changes,” said Professor James who is also a consultant clinical geneticist at the Parkville Familial Cancer Centre.

“If we want to use this information to help people, we have to know which of these genetic changes are truly disease-causing, and which are just ’normal’ variation in the DNA that doesn’t affect TP53 gene function.

“This new tool will make it easier for doctors and scientists to identify which genetic changes are likely to cause the disease and make sure that we can give the right advice to patients and hopefully greater certainty to families.”

The head of QIMR Berghofer’s Molecular Cancer Epidemiology Group and joint senior researcher on the study, Associate Professor Amanda Spurdle, said the new tool was only made possible due to large datasets made available via international collaboration.

“The more genetic data we gather, the better our understanding of the features of Li-Fraumeni syndrome,” Associate Professor Spurdle said.

“Collaborations are essential in science, especially in this case when there is so much unknown about this horrendous disease, and every bit of information counts. It is only by working with the best experts from all over the world that we will be able to keep providing insights into the life-changing consequences of TP53 genetic variants.

“We are lucky to be members of the ClinGen TP53 Expert panel, an FDA-approved international group that has also developed guidelines to better understand genetic changes in TP53. We hope that our tool, in addition to being useful for patients and doctors, will help inform and improve future versions of these guidelines.”

Management options for patients with disease-causing genetic changes include annual whole-body MRI screening, preventative surgeries, and in some cases different cancer treatments to deal specifically with their disease. For confirmed, genuine disease-causing variants, family members are also encouraged to get tested to ensure early detection and to improve chances of treatment and survival.

The research has been published in the journal Human Mutation.

The Australian-based research was funded by the National Health and Medical Research Council (NHMRC).