Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 91-101
Наследственный TP53-ассоциированный опухолевый синдром и медуллобластома у детей: вопросы диагностики и скрининга
https://doi.org/10.24287/1726-1708-2024-23-3-91-101Аннотация
На сегодняшний день вклад наследственных опухолевых синдромов в развитие онкологических заболеваний у детей очевиден, что определяет необходимость применения программ скрининга и выбора максимально эффективных методов противоопухолевой терапии. Одним из наиболее агрессивных наследственных опухолевых синдромов является ТР53-ассоциированный опухолевый синдром (hTP53rc, ранее – синдром Ли–Фраумени), характеризующийся высоким риском, ранним дебютом и повторными случаями злокачественных новообразований. В статье описаны современные данные о синдроме hTP53rc, особенности его клинического течения и международные рекомендации по обследованию и скринингу злокачественных новообразований у пациентов детского возраста. Представлен анализ регистра пациентов с рецидивирующими и рефрактерными формами медуллобластомы (n = 241) с оценкой частоты встречаемости случаев заболевания, ассоциированных с герминальными мутациями в гене TP53, особенностей их анамнеза жизни, влияния данного генетического события на исходы. Результаты проведенного исследования, а также данные международной литературы свидетельствуют о неблагоприятном течении опухолевых заболеваний, в том числе медуллобластомы, у данной когорты пациентов, тем не менее такие факторы, как ранний скрининг, динамическое наблюдение, своевременная и адекватная терапия, могут способствовать увеличению продолжительности их жизни. Исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «Национальный медицинский исследовательский центр им. В.А. Алмазова» Минздрава России.
Список литературы
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2. Ripperger T., Bielack S.S., Borkhardt A., Brecht I.B., Burkhardt B., Calaminus G., et al. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet A 2017; 173 (4):1017–37. DOI: 10.1002/ajmg.a.38142
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9. Kolodziejczak A.S., Guerrini-Rousseau L., Planchon J.M., Ecker J., Selt F., Mynarek M., et al. Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome. Neuro Oncol 2023; 25 (12): 2273–86. DOI: 10.1093/neuonc/noad114
10. Kratz C.P., Achatz M.I., Brugières L., Frebourg T., Garber J.E., Greer M.C., et al. Cancer Screening Recommendations for Individuals with Li–Fraumeni Syndrome. Clin Cancer Res 2017; 23 (11): e38–45. DOI: 10.1158/1078-0432.CCR-17-0408
11. Li F.P., Fraumeni J.F. Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 1969; 71: 747–52.
12. Li F.P., Fraumeni J.F. Jr, 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: 5358–62.
13. Malkin D., Li F.P., Strong L.C., Fraumeni J.F. Jr, Nelson C.E., Kim D.H., et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250 (4985): 1233–8. DOI: 10.1126/science.1978757
14. Frebourg T., Bajalica Lagercrantz S., Oliveira C., Magenheim R., Evans D.G.; European Reference Network GENTURIS. Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet 2020; 28: 1379–86. DOI: 10.1038/s41431-020-0638-4
15. 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. DOI: 10.1200/JCO.2014.59.5728
16. Степанов И.А., Васильева Е.В., Соколенко А.П., Имянитов Е.Н. Особенности нас ле дствен ного ТР53-ассоциированного опухолевого синдрома. Вопросы онкологии 2022; 68 (2): 140–8. DOI: 10.37469/0507-3758-2022-68-2-140-148
17. Aubrey B.J., Strasser A., Kelly G.L. Tumor-Suppressor Functions of the TP53 Pathway. Cold Spring Harb Perspect Med 2016; 6 (5): a026062. DOI: 10.1101/cshperspect.a026062
18. Olivier M., Goldgar D.E., Sodha N., Ohgaki H., Kleihues P., Hainaut P., Eeles R.A. Li–Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 2003; 63 (20): 6643–50.
19. Fortuno C., Lee K., Olivier M., Pesaran T., Mai P.L., de Andrade K.C., et al.; ClinGen TP53 Variant Curation Expert Panel. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. Hum Mutat 2021; 42 (3): 223–36. DOI: 10.1002/humu.24152
20. 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. DOI: 10.1038/ng.2532
21. Qian M., Cao X., Devidas M., Yang W., Cheng C., Dai Y., et al. TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children. J Clin Oncol 2018; 36 (6): 591–9. DOI: 10.1200/JCO.2017.75.5215
22. Waszak S.M., Northcott P.A., Buchhalter I., Robinson G.W., Sutter C., Groebner S., et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 2018; 19 (6): 785–98. DOI: 10.1016/S1470-2045(18)30242-0
23. Eeles R.A. Germline Mutations in the TP53 Gene in Breast and Other Cancers. Thesis. Institute of Cancer Research. University of London; 2000.
24. Carta R., Del Baldo G., Miele E., Po A., Besharat Z.M., Nazio F., et al. Cancer Predisposition Syndromes and Medulloblastoma in the Molecular Era. Front Oncol 2020; 10: 566822. DOI: 10.3389/fonc.2020.566822
25. Amadou A., Achatz M.I.W., Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li– Fraumeni syndrome. Curr Opin Oncol 2018; 30 (1): 23–9. DOI: 10.1097/CCO.0000000000000423
26. 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. DOI: 10.1016/S1470-2045(11)70119-X
27. Ballinger M.L., Mitchell G., Thomas D.M. Surveillance recommendations for patients with germline TP53 mutations. Curr Opin Oncol 2015; 27 (4): 332–7. DOI: 10.1097/CCO.0000000000000200
28. Daly M.B., Pal T., Berry M.P., Buys S.S., Dickson P., Domchek S.M., et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Langer C.E., Turner M.C., et al. Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomarkers Prev 2014; 23 (12): 2716–36. DOI: 10.1158/1055-9965.EPI-14-0207
29. Greer M.C., Voss S.D., States L.J. Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI. Clin Cancer Res 2017; 23 (11): e6–13. DOI: 10.1158/1078-0432.CCR-17-0515
30. Kanda T., Ishii K., Kawaguchi H., Kitajima K., Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 2014; 270: 834–41. DOI: 10.1148/radiol.13131669
31. Hu H.H., Pokorney A., Towbin R.B., Miller J.H. Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams. Pediatr Radiol 2016; 46: 1590–8. DOI: 10.1007/s00247-016-3646-3
32. Gopie J.P., Vasen H.F., Tibben A. Surveillance for hereditary cancer: does the benefit outweigh the psychological burden?--A systematic review. Crit Rev Oncol Hematol 2012; 83 (3): 329–40. DOI: 10.1016/j.critrevonc.2012.01.004
33. Lammens C.R., Aaronson N.K., Wagner A., Sijmons R.H., Ausems M.G., Vriends A.H., et al. Genetic testing in Li–Fraumeni syndrome: uptake and psychosocial consequences. J Clin Oncol 2010; 28 (18): 3008–14. DOI: 10.1200/JCO.2009.27.2112
34. Thariat J., Chevalier F., Orbach D., Ollivier L., Marcy P.Y., Corradini N., et al. Avoidance or adaptation of radiotherapy in patients with cancer with Li–Fraumeni and heritable TP53-related cancer syndromes. Lancet Oncol 2021; 22 (12): e562–74. DOI: 10.1016/S1470-2045(21)00425-3
35. Johnson K.J., Cullen J., Barnholtz-Sloan J.S., Ostrom Q.T., Langer C.E., Turner M.C., et al. Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomarkers Prev 2014; 23 (12): 2716–36. DOI: 10.1158/1055-9965.EPI-14-0207
36. Ostrom Q.T., Gittleman H., Fulop J., Liu M., Blanda R., Kromer C., et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro Oncol 2015; 17 Suppl 4 (Suppl 4): iv1–62. DOI: 10.1093/neuonc/nov189
37. [Electronic resource] Medulloblastoma Statistics. URL: https://medulloblastoma.org/medulloblastoma-statistics/. (accessed 19.06.2024).
38. Northcott P.A., Buchhalter I., Morrissy A.S., Hovestadt V., Weischenfeldt J., Ehrenberger T., et al. The whole-genome landscape of medulloblastoma subtypes. Nature 2017; 547 (7663): 311–7. DOI: 10.1038/nature22973
39. Louis D.N., Perry A., Wesseling P., Brat D.J., Cree I.A., Figarella-Branger D., et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 2021; 23 (8): 1231–51. DOI: 10.1093/neuonc/noab106
40. Zhukova N., Ramaswamy V., Remke M., Pfaff E., Shih D.J., Martin D.C., et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 2013; 31 (23): 2927–35. DOI: 10.1200/JCO.2012.48.5052
41. Le A.N., Harton J., Desai H., Powers J., Zelley K., Bradbury A.R., et al. Frequency of radiation-induced malignancies post-adjuvant radiotherapy for breast cancer in patients with Li–Fraumeni syndrome. Breast Cancer Res Treat 2020; 181 (1): 181–8. DOI: 10.1007/s10549-020-05612-7
42. Hendrickson P.G., Luo Y., Kohlmann W., Schiffman J., Maese L., Bishop A.J., et al. Radiation therapy and secondary malignancy in Li–Fraumeni syndrome: A hereditary cancer registry study. Cancer Med 2020; 9 (21): 7954–63. DOI: 10.1002/cam4.3427
Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 91-101
Heritable TP53-related cancer syndrome and medulloblastoma in children: diagnostic and screening issues
https://doi.org/10.24287/1726-1708-2024-23-3-91-101Abstract
Today, the contribution of hereditary tumor syndromes to the development of cancer in children is obvious, which determines the need for screening programs and selection of the most effective methods of anticancer therapy. One of the most aggressive hereditary tumor syndromes is heritable TP53-related cancer syndrome (hTP53rc, formerly known as Li–Fraumeni syndrome), characterized by a high risk, early onset and recurrent cases of malignant neoplasms in one patient. The article describes current data on hTP53rc syndrome and the features of its clinical course, and provides international recommendations for monitoring and cancer screening in pediatric patients with hTP53rc syndrome. As a clinical observation, we present an analysis of the registry of patients with relapsed and refractory forms of medulloblastoma (n = 241) with the assessment of its incidence in cases of germline mutations in the TP53 gene with the description of their medical history and the influence of this genetic event on the outcomes. The results of our study, as well as data from international literature, indicate unfavorable prognosis in tumors, including medulloblastoma, in patients with hTP53rc syndrome, however, such factors as early screening, surveillance and early and adequate therapy can help to increase their life expectancy. The study was approved by the Independent Ethics Committee and the Scientific Council of the Almazov National Medical Research Centre of Ministry of Healthcare of the Russian Federation.
References
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2. Ripperger T., Bielack S.S., Borkhardt A., Brecht I.B., Burkhardt B., Calaminus G., et al. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet A 2017; 173 (4):1017–37. DOI: 10.1002/ajmg.a.38142
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7. Soussi T., Kato S., Levy P.P., Ishioka C. Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum Mutat 2005; 25 (1): 6-17. DOI: 10.1002/humu.20114
8. Birch J.M., Hartley A.L., Tricker K.J., Prosser J., Condie A., Kelsey A.M., et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li–Fraumeni families. Cancer Res 1994; 54 (5): 1298–304.
9. Kolodziejczak A.S., Guerrini-Rousseau L., Planchon J.M., Ecker J., Selt F., Mynarek M., et al. Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome. Neuro Oncol 2023; 25 (12): 2273–86. DOI: 10.1093/neuonc/noad114
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14. Frebourg T., Bajalica Lagercrantz S., Oliveira C., Magenheim R., Evans D.G.; European Reference Network GENTURIS. Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet 2020; 28: 1379–86. DOI: 10.1038/s41431-020-0638-4
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18. Olivier M., Goldgar D.E., Sodha N., Ohgaki H., Kleihues P., Hainaut P., Eeles R.A. Li–Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 2003; 63 (20): 6643–50.
19. Fortuno C., Lee K., Olivier M., Pesaran T., Mai P.L., de Andrade K.C., et al.; ClinGen TP53 Variant Curation Expert Panel. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. Hum Mutat 2021; 42 (3): 223–36. DOI: 10.1002/humu.24152
20. 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. DOI: 10.1038/ng.2532
21. Qian M., Cao X., Devidas M., Yang W., Cheng C., Dai Y., et al. TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children. J Clin Oncol 2018; 36 (6): 591–9. DOI: 10.1200/JCO.2017.75.5215
22. Waszak S.M., Northcott P.A., Buchhalter I., Robinson G.W., Sutter C., Groebner S., et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 2018; 19 (6): 785–98. DOI: 10.1016/S1470-2045(18)30242-0
23. Eeles R.A. Germline Mutations in the TP53 Gene in Breast and Other Cancers. Thesis. Institute of Cancer Research. University of London; 2000.
24. Carta R., Del Baldo G., Miele E., Po A., Besharat Z.M., Nazio F., et al. Cancer Predisposition Syndromes and Medulloblastoma in the Molecular Era. Front Oncol 2020; 10: 566822. DOI: 10.3389/fonc.2020.566822
25. Amadou A., Achatz M.I.W., Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li– Fraumeni syndrome. Curr Opin Oncol 2018; 30 (1): 23–9. DOI: 10.1097/CCO.0000000000000423
26. 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. DOI: 10.1016/S1470-2045(11)70119-X
27. Ballinger M.L., Mitchell G., Thomas D.M. Surveillance recommendations for patients with germline TP53 mutations. Curr Opin Oncol 2015; 27 (4): 332–7. DOI: 10.1097/CCO.0000000000000200
28. Daly M.B., Pal T., Berry M.P., Buys S.S., Dickson P., Domchek S.M., et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Langer C.E., Turner M.C., et al. Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomarkers Prev 2014; 23 (12): 2716–36. DOI: 10.1158/1055-9965.EPI-14-0207
29. Greer M.C., Voss S.D., States L.J. Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI. Clin Cancer Res 2017; 23 (11): e6–13. DOI: 10.1158/1078-0432.CCR-17-0515
30. Kanda T., Ishii K., Kawaguchi H., Kitajima K., Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 2014; 270: 834–41. DOI: 10.1148/radiol.13131669
31. Hu H.H., Pokorney A., Towbin R.B., Miller J.H. Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams. Pediatr Radiol 2016; 46: 1590–8. DOI: 10.1007/s00247-016-3646-3
32. Gopie J.P., Vasen H.F., Tibben A. Surveillance for hereditary cancer: does the benefit outweigh the psychological burden?--A systematic review. Crit Rev Oncol Hematol 2012; 83 (3): 329–40. DOI: 10.1016/j.critrevonc.2012.01.004
33. Lammens C.R., Aaronson N.K., Wagner A., Sijmons R.H., Ausems M.G., Vriends A.H., et al. Genetic testing in Li–Fraumeni syndrome: uptake and psychosocial consequences. J Clin Oncol 2010; 28 (18): 3008–14. DOI: 10.1200/JCO.2009.27.2112
34. Thariat J., Chevalier F., Orbach D., Ollivier L., Marcy P.Y., Corradini N., et al. Avoidance or adaptation of radiotherapy in patients with cancer with Li–Fraumeni and heritable TP53-related cancer syndromes. Lancet Oncol 2021; 22 (12): e562–74. DOI: 10.1016/S1470-2045(21)00425-3
35. Johnson K.J., Cullen J., Barnholtz-Sloan J.S., Ostrom Q.T., Langer C.E., Turner M.C., et al. Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomarkers Prev 2014; 23 (12): 2716–36. DOI: 10.1158/1055-9965.EPI-14-0207
36. Ostrom Q.T., Gittleman H., Fulop J., Liu M., Blanda R., Kromer C., et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro Oncol 2015; 17 Suppl 4 (Suppl 4): iv1–62. DOI: 10.1093/neuonc/nov189
37. [Electronic resource] Medulloblastoma Statistics. URL: https://medulloblastoma.org/medulloblastoma-statistics/. (accessed 19.06.2024).
38. Northcott P.A., Buchhalter I., Morrissy A.S., Hovestadt V., Weischenfeldt J., Ehrenberger T., et al. The whole-genome landscape of medulloblastoma subtypes. Nature 2017; 547 (7663): 311–7. DOI: 10.1038/nature22973
39. Louis D.N., Perry A., Wesseling P., Brat D.J., Cree I.A., Figarella-Branger D., et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 2021; 23 (8): 1231–51. DOI: 10.1093/neuonc/noab106
40. Zhukova N., Ramaswamy V., Remke M., Pfaff E., Shih D.J., Martin D.C., et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 2013; 31 (23): 2927–35. DOI: 10.1200/JCO.2012.48.5052
41. Le A.N., Harton J., Desai H., Powers J., Zelley K., Bradbury A.R., et al. Frequency of radiation-induced malignancies post-adjuvant radiotherapy for breast cancer in patients with Li–Fraumeni syndrome. Breast Cancer Res Treat 2020; 181 (1): 181–8. DOI: 10.1007/s10549-020-05612-7
42. Hendrickson P.G., Luo Y., Kohlmann W., Schiffman J., Maese L., Bishop A.J., et al. Radiation therapy and secondary malignancy in Li–Fraumeni syndrome: A hereditary cancer registry study. Cancer Med 2020; 9 (21): 7954–63. DOI: 10.1002/cam4.3427
