Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children108810.24287/j.1088LITERATURE REVIEWОБЗОР ЛИТЕРАТУРЫReview ArticleHematologic malignancies in Li–Fraumeni syndromeГематологические злокачественные новообразования при синдроме Ли–Фраумениhttps://orcid.org/0000-0002-1085-4646KazakovaA. N.КазаковаА. Н.
Russian Federation

MD in Clinical Laboratory Medicine, Deputy Head of the Laboratory of Cytogenetics and Molecular Genetics

врач клинической лабораторной диагностики, заместитель заведующего лабораторией цитогенетики и молекулярной генетики

anna.kazakova@dgoi.ruhttps://orcid.org/0000-0003-0098-919XItovA. B.ИтовА. Б.
Russian Federation
anna.kazakova@dgoi.ruThe Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России140420262512032120602202606032026Copyright ©; 2026, «D. Rogachev NMRCPHOI»Copyright ©; 2026, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2026«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/1088

Li–Fraumeni Syndrome (LFS) is a rare, autosomal dominant, highly penetrant cancer predisposition syndrome caused by germline mutations in the TP53 (Tumor Protein 53) gene. The classic tumor spectrum of LFS includes adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft tissue sarcomas. Hematologic malignancies (HMs) occur in 4–12% of LFS cases, with a predominance of acute lymphoblastic leukemia characterized by a specific cytogenetic variant – a hypodiploid karyotype. Myelodysplastic syndromes and acute myeloid leukemias are less common and are typically secondary to prior cytotoxic therapy. Given the unfavorable prognosis of HMs in LFS and the necessity of bone marrow transplantation as a curative treatment modality, early identification of this patient group and the selection of an optimal donor who does not carry germline TP53 mutations are of high importance. This review presents the fundamental principles of the pathogenetic basis of LFS and clinical screening criteria, providing a detailed description of the spectrum of HMs in LFS, with specific focus on the clinical and laboratory features of the most common variants.

Синдром Ли–Фраумени (СЛФ) – редкий аутосомно-доминантный, высокопенетрантный синдром предрасположенности к развитию злокачественных новообразований, обусловленный герминальными мутациями в гене TP53 (Tumor Protein 53). Классический спектр опухолей при СЛФ включает адренокортикальные карциномы, рак молочной железы, опухоли центральной нервной системы, остеосаркомы и саркомы мягких тканей. Гематологические злокачественные новообразования (ГЗН) встречаются в 4–12% СЛФ, среди них превалируют острые лимфобластные лейкозы с характерным цитогенетическим вариантом – гипоплоидным кариотипом, реже встречаются миелодиспластические синдромы и острые миелоидные лейкозы, как правило, индуцированные предшествующей цитотоксической терапией. Учитывая неблагоприятный прогноз ГЗН при СЛФ и необходимость трансплантации костного мозга как одного из куративных методов терапии, крайне важными являются раннее выявление данной группы пациентов и выбор оптимального донора, не являющегося носителем герминальных мутаций TP53. В настоящем обзоре представлены основные положения о патогенетических основах СЛФ, клинических критериях скрининга, дано подробное описание спектра ГЗН при СЛФ с детализацией клинико-лабораторных особенностей наиболее часто встречающихся вариантов.

Li–Fraumeni syndromegermline TP53 mutationshematologic malignancieschildrenсиндром Ли–Фрауменигерминальные мутации гена TP53гематологические злокачественные новообразованиядетиOrphanet: Li–Fraumeni syndrome [Electronic resource]. URL: https://www.orpha.net/en/disease/ detail/524?mode = name&name = LiFraumeni%20syndrome (accessed 13.12.2025).Schneider K., Zelley K., Nichols K. E., Schwartz Levine A., Garber J. Li–Fraumeni syndrome. GeneReviews® Adam M.P., Bick S., Mirzaa G.M., Pagon R.A., Wallace S.E., Amemiya A. (eds.). Seattle (WA). University of Washington, Seattle, 1993.Bougeard G., Renaux-Petel M., Flaman J.-M., Charbonnier C., Fermey P., Belotti M., et al. Revisiting Li–Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 2015;33(21): 2345–52.De Andrade K.C., Khincha P.P., Hatton J.N., Frone M.N., Wegman-Ostrosky T., Mai P.L. et al. Cancer incidence, patterns, and genotype–phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol 2021;22(12): 1787–98.Penkert J., Strüwe F.J., Dutzmann C.M., Doergeloh B.B., Montellier E., Freycon C. et al. Genotype-phenotype associations within the Li–Fraumeni spectrum: a report from the German Registry. J Hematol Oncol 2022;15(1):107.Frebourg T., Bajalica Lagercrantz S., Oliveira C., Magenheim R., Evans D.G. Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet 2020;28(10):1379–86.Vagher J., Zakas A., Donovan L., Shoger K., Naumer A., Bly J. et al. Hematologic Malignancy frequency, phenotypes, and outcomes in Li–Fraumeni syndrome. JCO Precis Oncol 2025;9:e2400860.Fiala E., Breen K., Kennedy J., Abbass M., Carlo M., Liu Y. et al. Spectrum, molecular features, and clinical outcomes of hematologic malignancies and clonal hematopoiesis in Li–Fraumeni syndrome. Blood 2025;146(Suppl 1):3220.Dimopoulos Y.P., Wang W., Wang S.A., Loghavi S., DiNardo C.D., Gerstein Y. et al. The spectrum of hematologic neoplasms in patients with Li–Fraumeni syndrome. Am J Hematol 2024;99(12):2416–9.Comeaux E.Q., Mullighan C.G. TP53 mutations in hypodiploid acute lymphoblastic leukemia. Cold Spring Harb Perspect Med 2017;7(3):a026286.Kratz C.P., Freycon C., Maxwell K.N., Nichols K.E., Schiffman J.D., Evans D.G. 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 2021;7(12):1800–5.Li F.P., Fraumeni J.F. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 1969;71(4):747–52.Li F.P., Fraumeni J.F., Mulvihill J.J., Blattner W.A., Dreyfus M.G., Tucker M.A. et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48(18):5358–62.Malkin D., Li F.P., Strong L.C., Fraumeni J.F., Nelson C.E., Kim D.H. et al. Germline p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250(4985): 1233–8.Yonish-Rouach E., Resnitzky D., Lotem J., Sachs L., Kimchi A., Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 1991;352(6333):345–7.Lane D.P. Cancer. p53, guardian of the genome. Nature 1992;358(6381):15–6.Kastenhuber E.R., Lowe S.W. Putting p53 in context. Cell 2017;170(6):1062–78.Boutelle A.M., Attardi L.D. p53 and tumor suppression: it takes a network. Trends Cell Biol 2021;31(4):298–310.Wang H., Guo M., Wei H., Chen Y. Targeting p53 pathways: mechanisms, structures and advances in therapy. Signal Transduct Target Ther. 2023;8(1):92.Han C.W., Lee H.N., Jeong M.S., Park S.Y., Jang S.B. Structural basis of the p53 DNA binding domain and PUMA complex. Biochem Biophys Res Commun. 2021;548:39–46.Sullivan K.D., Galbraith M.D., Andrysik Z., Espinosa J.M. Mechanisms of transcriptional regulation by p53. Cell Death Differ 2018;25(1):133–43.Walker K.K., Levine A.J. Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc Natl Acad Sci 1996;93(26):15335–40.Weinberg R.L., Veprintsev D.B., Fersht A.R. Cooperative binding of tetrameric p53 to DNA. J Mol Biol 2004;341(5):1145–59.Laptenko O., Tong D.R., Manfredi J., Prives C. The Tail that wags the dog: how the disordered C-terminal domain controls the transcriptional activities of the p53 tumor-suppressor protein. Trends Biochem Sci 2016;41(12):1022–34.Retzlaff M., Rohrberg J., Küpper N.J., Lagleder S., Bepperling A., Manzenrieder F. et al. The regulatory domain stabilizes the p53 tetramer through intersubunit contacts with the DNA-binding domain. J Mol Biol 2013;425(1):144–55.Hernández Borrero L.J., El-Deiry W.S. Tumor suppressor p53: biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer 2021;1876(1):188556.Chompret A., Brugières L., Ronsin M., Gardes M., Dessarps-Freichey F., Abel A. et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer 2000;82(12):1932–7.Correa H. Li–Fraumeni syndrome. J Pediatr Genet 2016;5(2):84–8.Ward A., Farengo-Clark D., McKenna D.B., Safonov A., Good M., Le A. et al. Clinical management of TP53 mosaic variants found on germline genetic testing. Cancer Genet 2024;284–285:43–7.Castillo D., Yuan T.-A., Nehoray B., Cervantes A., Tsang K.K., Yang K. et al. Clonal hematopoiesis and mosaicism revealed by a multi-tissue analysis of constitutional TP53 status. Cancer Epidemiol Biomark Prev 2022;31(8):1621–9.Tornesello M.L. TP53 mutations in cancer: molecular features and therapeutic opportunities (review). Int J Mol Med 2024;55(1):7.The TP53 database [Electronic resource]. URL: https://tp53.cancer.gov/ (accessed 02.01.2026).Olivier M., Hollstein M., Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010;2(1):a001008.Montellier E., Lemonnier N., Penkert J., Freycon C., Blanchet S., Amadou A. et al. Clustering of TP53 variants into functional classes correlates with cancer risk and identifies different phenotypes of Li–Fraumeni syndrome. iScience 2024;27(12):111296.Ruijs M.W.G., Schmidt M.K., Nevanlinna H., Tommiska J., Aittomäki K., Pruntel R. et al. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li–Fraumeni syndrome and related phenotypes. Eur J Hum Genet 2007;15(1):110–4.Tabori U., Nanda S., Druker H., Lees J., Malkin D. Younger age of cancer initiation is associated with shorter telomere length in Li–Fraumeni syndrome. Cancer Res 2007;67(4): 1415–8.Lee J.W. Li–Fraumeni syndrome: current strategies and future perspectives. J Korean Neurosurg Soc 2025;68(3):305–10.Montellier E., Manches O., Gaucher J., Freycon C., Hoyos D., Blanchet S. et al. Neoantigenic properties of TP53 variants influence cancer risk in individuals with Li–Fraumeni syndrome. eBioMedicine 2026;123:106065.Guidelines detail [Electronic resource]. NCCN URL: https://www.nccn.org/guidelines/guidelines-detail?category = 2&id = 1545 (accessed 06.01.2026).Carroll A.J., Shago M., Mikhail F.M., Raimondi S.C., Hirsch B.A., Loh M.L. et al. Masked hypodiploidy: hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: a report from the children’s oncology group. Cancer Genet 2019;238:62–8.Ольшанская Ю.В., Солдаткина О.И., Никитин Е.Н., Тимофеева Н.М., Казакова А.Н., Быданов О.И. и др. Гиподиплоидный кариотип при острых лимфобластных лейкозах из В-линейных предшественников у детей. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2021;20(2):97–110. [Olshanskaya Yu.V., Soldatkina O.I., Nikitin E.N., Timofeyeva N.M., Kazakova A.N., Bydanov O.I. et al. A hypodiploid karyotype in childhood B-cell precursor acute lymphoblastic leukemia. Pediatric Hematology/Oncology and Immunopathology 2021;20(2):97–110 (In Russ.)].Harrison C.J., Moorman A.V., Broadfield Z.J., Cheung K.L., Harris R.L., Reza Jalali G. et al. Three distinct subgroups of hypodiploidy in acute lymphoblastic leukemia. Br J Haematol 2004;125(5):552–9.Winter G., Kirschner-Schwabe R., Groeneveld-Krentz S., Escherich G., Möricke A., von Stackelberg A. et al. Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li–Fraumeni syndrome. Leukemia 2021;35(5): 1475–9.Holmfeldt L., Wei L., Diaz-Flores E., Walsh M., Zhang J., Ding L. et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 2013;45(3):242–52.Mühlbacher V., Zenger M., Schnittger S., Weissmann S., Kunze F., Kohlmann A. et al. Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%. Genes Chromosomes Cancer 2014;53(6):524–36.Donehower L.A., Soussi T., Korkut A., Liu Y., Schultz A., Cardenas M. et al. Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep 2019;28(5):1370–84.e5.Hanel W., Moll U.M. Links between mutant p53 and genomic instability. J Cell Biochem 2012;113(2):433–9.Thompson S.L., Compton D.A. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol 2010;188(3): 369–81.Jones M.J.K., Jallepalli P.V. Chromothripsis: chromosomes in crisis. Dev Cell 2012;23(5):908–17.Holmfeldt L., Mullighan C.G. Generation of human acute lymphoblastic leukemia xenografts for use in oncology drug discovery. Curr Protoc Pharmacol 2015;68(1):14. 32.1–19.Swaminathan M., Bannon S.A., Routbort M., Naqvi K., Kadia T.M., Takahashi K. et al. Hematologic malignancies and Li–Fraumeni syndrome. Mol Case Study 2019;5(1):a003210.p53 biology and reactivation for improved therapy in MDS and AML – PMC [Electronic resource]. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC10936007/ (accessed 06.01.2026).Волчков Е.В., Абугова Ю.Г., Бренинг К.Р., Абрамов Д.С., Фоминых В.В., Сенченко М.А. и др. Прогностическое значение статуса гена TP53 у детей с лимфомой Беркитта на протоколе В-НХЛ-2010М. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2024;23(1):56–62. [Volchkov E.V., Abugova Yu.G., Brenning K.R., Abramov D.S., Fominykh V.V., Senchenko M.A. et al. The prognostic value of TP53 mutational status in children with Burkitt lymphoma treated according to the B-NHL-2010M protocol. Pediatric Hematology/Oncology and Immunopathology 2024;23(1):56–62. (In Russ.)].Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome – PMC [Electronic resource]. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC11022827/ (accessed 11.01.2026).Zhao Y., Chen W., Yu J., Pei S., Zhang Q., Sh, J, et al. TP53 in MDS and AML: biological and clinical advances. Cancer Lett 2024;588:216767.Cazzola A., Schlegel C., Jansen I., Bochtler T., Jauch A., Krämer A. TP53 deficiency permits chromosome abnormalities and karyotype heterogeneity in acute myeloid leukemia. Leukemia 2019;33(11):2619–27.Newman A.M., Zaka M., Zhou P., Blain A.E., Erhorn A., Barnard A. et al. Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma. Leukemia 2022;36(3):781–9.Villani A., Tabori U., Schiffman J., Shlien A., Beyene J., Druker H. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011;12(6): 559–67.Villani A., Shore A., Wasserman J.D., Stephens D., Kim R.H., Druker H. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: 11-year follow-up of a prospective observational study. Lancet Oncol 2016;17(9):1295–305.Association L.F.S. 2025 updated screening guidelines for Li–Fraumeni syndrome (LFS). LFS Assoc. 2025.Oba L., Best A.F., Mai P.L., Achatz M.I., Albert P.S., Savage S.A. et al. Utility of interim blood tests for cancer screening in Li–Fraumeni syndrome. Fam Cancer 2022;21(3): 333–6.