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Research Highlight | May 09, 2023

Scientists find Li-Fraumeni syndrome defined by more than one gene; expansion of genetic and epigenetic testing will benefit patients

Li-Fraumeni syndrome (LFS) is a rare, inherited condition causing cancer in nearly all those affected, with many developing multiple cancers before the age of 45. And while researchers can predict cancer development in some patients – which contributes to early tumour detection and risk reduction – many slip through the cracks.

Dr. David Malkin, a celebrated researcher at The Hospital for Sick Children in Toronto, is leading a team of researchers whose identification of additional LFS biomarkers may begin to change this.

“In our study we identified alternative cancer-causing aberrations in patients that lack a germline TP53 variant, which will enable the diagnosis of LFS in patients that would have been missed through standard screening procedures,” says Valli Subasri, a graduate researcher at the University of Toronto and the paper’s first author.

Until now, diagnosing this syndrome involved screening for germline pathogenic variants of the TP53 tumour suppressor gene. However, this is only accurate in diagnosing patients fitting the clinical definition of LFS in roughly 70 per cent of cases. According to Subasri, “it is not understood why the remaining 30 per cent of patients lack a TP53 variant. Even among variant TP53 carriers, it remains unclear why approximately 20 per cent remain cancer free.”

To improve the accuracy of existing LFS screening protocols in patients with the TP53 variant, the team identified a simultaneous germline hit that further increases the likelihood of cancer and decreases overall survival. They also identified modifiers, or resilience mechanisms, in the Wnt signalling pathway that, in contrast, are associated with a reduced cancer risk. These resilience mechanisms may explain why some patients with a germline TP53 variant never develop cancer.

“By identifying alternative driver and modifier events, our findings highlight the immense benefits of expanding genetic and epigenetic testing of LFS patients beyond TP53,” says Subasri. In doing so, future studies may be able to explore how cancer can even be prevented in LFS patients.

Finally, by leveraging the non-coding genome and methylome to identify inherited epimutations associated with cancer, the team built a machine learning model to predict cancer risk in patients with LFS.

Together, their findings will contribute to the early detection and prevention of cancer in those with LFS, and further the understanding that this hereditary cancer syndrome needs to be viewed in a holistic manner, rather than as a disorder defined by a single gene. 


Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome


Vallijah Subasri, Nicholas Light, Nisha Kanwar, Jack Brzezinski, Ping Luo, Jordan R. Hansford, Elizabeth Cairney, Carol Portwine, Christine Elser, Jonathan L. Finlay, Kim E. Nichols, Noa Alon, Ledia Brunga, Jo Anson, Wendy Kohlmann, Kelvin C. de Andrade, Payal P. Khincha, Sharon A. Savage, Joshua D. Schiffman, Rosanna Weksberg, Trevor J. Pugh, Anita Villani, Adam Shlien, Anna Goldenberg, and David Malkin


This study was partially funded by a Terry Fox New Frontiers Program Project Grant in Early Detection and Prevention of Cancer In Li Fraumeni Syndrome