HMN 2026: How the immune system may shape inherited cancer risk

Li-Fraumeni syndrome is a rare hereditary disease that significantly increases the risk of developing cancer. Almost all affected individuals receive a cancer diagnosis at least once in their lifetime. A new study suggests that the immune system is partly responsible for why cancer occurs at very different ages and in different forms. This opens up new perspectives for personalized treatment approaches in the future. The international team has published their findings in eBioMedicine.

Cross-border research may explain variable cancer risk

“Li-Fraumeni syndrome is caused by inherited changes in a gene called TP53, which normally helps protect the body from cancer,” explains Professor Christian Kratz, Director of the Department of Pediatric Hematology and Oncology at Hannover Medical School (MHH) and co-initiator of the study. “Those affected have a high lifetime risk of developing cancer. In addition, individual cancer risk can vary significantly even within the same family.”

In the cross-national study, led by representatives Université Grenoble Alpes/ Inserm U1209 IAB, the Université de Rouen Normandie/ Inserm U1245 CBG in France and the MHH, the researchers wanted to gain a better understanding of the causes of this variability.

Immune cells can detect genetic changes

The study investigated whether the body’s own immune system could play a role in the development of cancer. “We focused on how different changes in the TP53 gene are recognized by immune cells,” explains Emilie Montellier of the Inserm. “Some altered forms of the p53 protein can produce small fragments that the immune system recognizes as abnormal, which is associated with a reduced risk of cancer.”

By analyzing genetic and clinical data from thousands of people with Li-Fraumeni syndrome, the researchers identified a clear pattern: individuals who carried variants in the TP53 gene that were more likely to be recognized by the immune system tended to develop cancer later in life. They were also less likely to develop some of the cancers most commonly associated with Li-Fraumeni syndrome, such as bone and soft tissue sarcomas.

Reduced overall risk of cancer

The findings suggest that the immune system influences how inherited cancer risk develops over the course of a person’s life. Although immune recognition does not prevent cancer from developing in people with Li-Fraumeni syndrome, it may help reduce overall risk by delaying the onset of cancer or changing the type of cancers that occur.

“Our work has no immediate impact on medical care, but it opens up new possibilities for personalized approaches in the future,” explains Gaëlle Bougeard of the University of Rouen Normandy. “Information about a person’s specific TP53 variant and immune system background could help doctors better tailor cancer monitoring and prevention strategies in the future.”

“More generally, these results show how interactions between genetic variations and the immune system can influence cancer risk—not only in Li-Fraumeni syndrome, but possibly also in other hereditary cancers,” adds Professor Kratz.

An obituary for Professor Pierre Hainaut, who played a key role in advancing the study and tragically passed away after submitting the manuscript, can be found here.

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