Клинические случаи синдрома Ли-Фраумени в детской онкологической практике

Статья в Elpub

Онкопедиатрия. 2016; 3: 207-213

Клинические случаи синдрома Ли-Фраумени в детской онкологической практике

Козлова В. М., Валиев Т. Т., Казубская Т. П., Ковалёва Я. В., Лукьянова Е. Н., Стрельников В. В., Поспехова Н. И., Михайлова С. Н., Заева Г. Е., Любченко Л. Н.

https://doi.org/10.15690/onco.v3i3.1599

Аннотация

В статье описаны три случая синдрома Ли-Фраумени у детей с редкой опухолью головного мозга и с первично-множественными опухолями. Представлены различные методы молекулярной диагностики синдрома, ассоциированного с герминальной мутацией гена ТР53. Проанализирован гетерогенный характер клинического проявления синдрома, его взаимосвязь с видом мутаций в гене ТР53, мониторинг лиц-носителей мутантного ТР53-генотипа. С учетом генетических особенностей синдрома Ли-Фраумени приведены возможности проведения патогенетически оправданной таргетной терапии, направленной на модификацию белка р53.

Список литературы

1. Li FP, Fraumeni JF.Jr. Prospective study of a family cancers syndrome. JAMA. 1982;247:2692–2694.

2. Malkin D, Li F, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250:1233–1238.

3. Schlegelberger B, Kreipe H, et al. A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. Pediatr Blood Cancer. 2015;62:481–4.

4. Evans DG, Wu CL, Birch JM. BRCA2: A cause of Li-Fraumenilike syndrome. J Med Genet. 2008;45:62–63.

5. Hisada M, Garber JE, Fung CY, Fraumeni JF.Jr, Li FP. Multiple primary cancers in families with Li- Fraumeni syndrome. J Nat Cancer Inst. 1998;90:606–611.

6. Olivier M, Goldgar DE, Sodha N, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003;63(20):6643–50.

7. Bates S, Vousden KH. Mechanisms of p53-mediated apoptosis. Cell Mol Life Sci. 1999 Jan;55(1):28– 37.

8. Bates S, Hickman ES, Vousden KH. Reversal of p53-induced cell-cycle arrest. Mol Carcinog. 1999 Jan;24(1):7–14.

9. Копнин Б.П, Копнин П.Б., Хромова Н.В., Агапова Х.С.М ноголикий р53: разнообразие форм, функций, опухоль-супрессирующих и онкогенных активностей. Клиническая онкогематология. 2008;1:2–9.

10. Soussi T, B´eroud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nature Reviews Cancer. 2001;1(3):233–240.

11. Agarwal R, Liebe S, Turski ML, et al. Targeted therapy for hereditary cancer syndromes: hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and Li-Fraumeni syndrome. Discov Med. 2014;18(101):331–9.

12. Tazawa H, Kagawa S, Fujiwara T, et al. Advances in adenovirus- mediated p53 cancer gene therapy. Expert Opin Biol Ther. 2013 Nov;13(11):1569–83.

13. Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–317.

14. Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol. 2013;15:2–8.

15. Chen GX, Zhang S, He XH, et al. Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives. Onco Targets Ther. 2014;7:1901–9.

16. Senzer N, Nemunaitis J, Nemunaitis M, et al. p53 therapy in a patient with Li-Fraumeni syndrome. Mol Cancer Ther. 2007;6(5):1478–82.

17. Chène P. The role of tetramerization in p53 function. Oncogene. 2001 May 10;20(21):2611–2617.

18. Kamada R, Nomura T, Anderson CW, Sakaguchi K. Cancerassociated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation. J Biol Chem. 2011 Jan 7;286(1):252–258.

19. Немцова М.В., Танас А.С., Алексеева Е.А. и соавт. Соматические и герминальные мутации при раке желудка. Молекулярная медицина. 2015;4:28–34.

20. Sarraf P, Mueller E, Smith WM, et al. Loss-of-function mutations in PPAR-gamma associated with human colon cancer. Mol Cell. 1999;3:799–804.

21. Valve R, Sivenius K, Miettinen R, et al. Two polymorphisms in the peroxisome proliferator- activated receptor-gamma gene are associated with severe overweight among obese women. J Clin Endocr Metab. 1999;84:3708–3712.

22. Zhou X-P, Smith WM, Gimm O, et al. Over-representation of PPAR-gamma sequence variants in sporadic cases of glioblastoma multiforme: preliminary evidence for common low penetrance modifiers for brain tumour risk in the general population. J Med Genet. 2000;37:410–414.

Oncopediatrics. 2016; 3: 207-213

Li-Fraumeni Syndrome: Clinical Cases in Pediatric Oncology Practice

Kozlova V. M., Valiev T. T., Kazubskaya T. P., Kovaleva Ya. V., Lukyanova E. N., Strelnikov V. V., Pospekhova N. I., Mikhailova S. N., Zaeva G. E., Lyubchenko L. N.

https://doi.org/10.15690/onco.v3i3.1599

Abstract

The article describes three cases of Li-Fraumeni syndrome in children with rare brain tumor and multiple primary tumors. We present various molecular diagnostics methods for the syndrome associated with germline mutation in TP53 gene. We have analyzed the heterogeneous nature of clinical manifestations of the syndrome, relationship of the syndrome to the types of mutations in the TP53 gene, the monitoring of individuals, who carrying the mutant TP53 genotype. By hereditary features of Li-Fraumeni syndrome, targeted therapeutic approaches to protein p53 modification are presented.

References