Clinical and genetic features of patients with Li–Fraumeni syndrome: experience of Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov

Introduction. Li–Fraumeni syndrome (LFS) is associated with a pathogenic variant in the TP53 gene and the development of malignant tumors (MT) in various locations. Moreover, the spectrum of MT is characterized by wide heterogeneity even within a single family. The distribution, type, and position of mutations in the TP53 gene are also variable, and the gene penetrance is incomplete, leading to the presence of healthy carriers of pathogenic variants. Genetic diagnosis of LFS is crucial for the early detection of neoplasms, as well as for the selection of treatment for the primary tumor.

The aim of the study was to search for clinical and genetic correlations between pathogenic variants of TP53 and the characteristics of the associated malignant neoplasms (severity of clinical manifestations) for the subsequent classification of patients based on the individual risk of developing MT and the formation of a dynamic observation strategy.

Materials and methods. The study included 25 children with confirmed LFS between 2003 and 2025. All patients received treatment at the Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov. Molecular genetic testing was performed using the next-generation sequencing method using a panel of onco-associated genes. Gene rearrangement analysis was performed using multiplex ligation-dependent probe amplification. Segregation analysis for 30 relatives from 16 families was performed using the Sanger sequencing method.

Results. Genetic testing revealed 13 mutations within exons 3–8, as well as the I332Pfs*14 deletion in exon 10 of the TP53 gene. Familial LFS was identified in 13 of 16 families. Penetrance was 75.7 %, with primary multiple tumors identified in 5 (20 %) children and 7 (58 %) patients over 18 years of age. Analysis of pediatric LFS patients allowed us to identify two clinical and genetic groups. The first group of children with highly penetrant pathogenic variants Q165*, R175H, R248W, R273C, R306*, exon 10 deletion, and exon 3 splice site mutation was associated with mesenchymal neoplasms of earlier onset and a high risk of developing second tumors. The second group includes lowpenetrance variants R110C, R196Q, R196P, and S215I, identified in children with aggressive, late-onset, low-risk nervous system tumors. The high-penetrance variant P47R*fs76 was found in one family in children who could be classified into the two aforementioned clinical and genetic groups.

Among adult patients, six out of eight women carrying mutations in the TP53 gene were diagnosed with breast cancer, four of them had bilateral tumors. Three patients with bilateral breast cancer and variants G108_F109 del, R175H, and R306* were later diagnosed with MT of other localizations. In men, LFS was manifested by the development of sarcomas after 18 years (P47R*fs76 and R306*), as well as rarer neoplasms such as rectal cancer, lymphoma, and brain tumor (R248W).

Conclusion. A genetic study allows not only to confirm the diagnosis of LFS, but also to stratify patients into risk groups for developing certain diseases, which can be used to draw up an individual follow-up plan. Preventive mastectomy may also be considered for women with LFS. Incomplete penetrance and a variety of clinical manifestations indicate the possible influence of modifying factors, which necessitates further investigation of this phenomenon and minimization of contact with carcinogenic factors for carriers of pathogenic variants in the TP53 gene.

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