Disease severity of patients with Li-Fraumeni syndrome classified for the first time

An international team succeeds on the path to better understand the manifestations of this hereditary disease.

"Li-Fraumeni spectrum" to facilitate search for factors that lead to different courses of the disease

International team succeeds in taking an important step towards a better understanding of the manifestations of this hereditary disease.

Li-Fraumeni syndrome (LFS) is associated with a drastically increased lifelong risk of a broad spectrum of cancers. It is one of the cancer predisposition syndromes and is caused by pathological genetic changes in the TP53 gene. A definition reflecting the broad spectrum of the disease has been lacking and factors leading to differences in the disease have been largely unknown.

An international research consortium involving Professor Dr. Peter Christian Kratz, Hannover Medical School (HMS), Germany, Professor Pierre Hainaut, Institute for Advanced Biosciences, Grenoble, France, Professor David Malkin, Hospital for Sick Children, Toronto, Canada, and other researchers has now developed a classification under the term "Li-Fraumeni spectrum" that comprehensively reflects the disease severity and facilitates the search for factors that lead to different disease courses. The research results were published in the renowned journal JAMA Oncology.


Professor Dr. Christian Kratz, Director of the Department of Paediatric Haematology and Oncology at the HMS with the classification model
Source: Karin Kaiser/ HMS

"A new classification was necessary"

Clinical and genetic criteria can be used to identify people who are most likely to have underlying LFS. However, with increasing research into the gene, it has become clear in recent years that people who do not fulfil these criteria can also be affected by LFS. Diagnosis is essential as regular screening for cancer improves the prognosis of those affected. "The reclassification was necessary to describe the evolving spectrum of LFS. It draws on established clinical criteria developed over decades and takes into account cancer risk-modifying factors without the need to specify them. At the same time, it can facilitate the search for factors that influence the severity of the disease in those affected with LFS," says Professor Kratz, Director of the Department of Paediatric Oncology and Haematology at HMS.

3,034 patients from 1,282 families analysed

The research team used the classification to analyse data from 3,034 patients from 1,282 families with a hereditary TP53 variant from the International Agency for Research on Cancer database from November 2020 to March 2021. They identified differences between the TP53 variants in patients with severe disease compared to those with milder courses.

Differences in tumour characteristics

Of the 3,034 people, 2,139 (70.5%) met the LFS genetic test criteria or developed cancer before the age of 18. 149 people (4.9%) were unaffected carriers and blood relatives of these patients. 678 people (22.3%) did not meet the LFS genetic test criteria and did not develop cancer before the age of 18. 33 people (1.1%) were cancer-free carriers and relatives of these patients. While the lifetime risk was about the same for those who did or did not meet the LFS genetic cancer criteria, there were differences in tumour characteristics. "Patients who met the LFS genetic testing criteria were more likely to have early adrenal, brain, connective tissue and bone tumours, while TP53 variant carriers who did not meet the genetic testing criteria had a higher proportion of breast and other cancers, 45% of which occurred after the age of 45," points out Professor Hainaut of the Institute for Advanced Biosciences, Grenoble, France.

The new LFS classification is a step towards better understanding the factors that lead to different manifestations of the syndrome. "The results of this study provide a rational basis for more accurately counselling patients with TP53 variants regarding their own cancer risk and the cancer risk of their family members, as well as for more targeted tumour screening strategies," says Professor Malkin of the Hospital for Sick Children, Toronto. "The approach we have taken could be a model for the reclassification of other cancer predisposition syndromes."

In addition to Germany, France and Canada, researchers from Brazil, England and the USA were involved. The study was funded by the German Childhood Cancer Foundation, the German Federal Ministry of Education and Research, the Canadian Institutes of Health Research and the Terry Fox Research Institute, among others.

Kratz CP, Freycon C, Maxwell KN, et al. Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set: An International Agency for Research on Cancer TP53 Database Analysis. JAMA Oncol. Published online October 28, 2021. doi:10.1001/jamaoncol.2021.4398