Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2018; 17: 43-49
Прогностическое значение молекулярно-генетических и клинических характеристик медуллобластом группы SHH
https://doi.org/10.24287/1726-1708-2018-17-3-43-49Аннотация
Медуллобластомы группы SHH – гетерогенные опухоли, которые отличаются по своим молекулярно-генетическим характеристикам и прогнозу заболевания. Цель исследования: анализ клинических и молекулярно-генетических факторов прогноза у пациентов с медуллобластомой группы SHH. В ретроспективно-проспективное исследование включили 28 пациентов (20 мальчиков и 8 девочек) с медуллобластомой группы SHH, в том числе 15 детей младше 3 лет и 13 – старше 3 лет. Проводены оценка экспрессии генов методом Nanostring и иммуногистохимический анализ. Поиск мутаций в гене TP53 был выполнен методом секвенирования по Сэнгеру. Проанализированы клинические и молекулярно-генетические факторы прогноза заболевания. У всех пациентов с мутацией в гене TP53 (n = 3) прогноз был неблагоприятным. У детей старшего возраста (³ 3 лет) отмечено большее количество неблагоприятных событий по сравнению с детьми младше 3 лет: бессобытийная выживаемость составила 49,2 ± 31,3% и 78,8 ± 13,9% соответственно. Рецидивы выявлены у 7 (25%) пациентов, при этом у детей младшего возраста в большинстве случаев противорецидивная терапия оказалась эффективной. Мутации в гене TP53 определяют плохой прогноз в группе SHH. Необходим поиск дополнительных молекулярно-генетических факторов прогноза для дальнейшей оптимизации терапии.
Список литературы
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2. Taylor M.D., Northcott P.A., Korshunov A., Remke M., Cho Y.J., Clifford S.C., et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012; 123 (4): 465–72.
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12. Tabori U., Baskin B., Shago M., Alon N., Taylor M.D., Ray P.N., et al. Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 2010; 28 (8): 1345–50.
13. 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.
14. Ramaswamy V., Remke M., Bouffet E., Baile S., Clifford S.C., Doz F., et al. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol 2016; 131: 821–31.
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19. Abdelbaki M., Boue D., Finlay J., Kieran M. Desmoplastic medulloblastoma in young children: a management dilemma. Neuro Oncol 2018 Jul 5; 20 (8): 1026–33.
20. Upadhyaya S.A., Robinson G., Orr B., Onar-Thomas A., Billups C., Bowers D., et al. Outcomes for nonmetastatic Desmoplastic/Nodular infant Medul-loblastoma treated with reduced intensity chemotherapy and oral maintenance chemotherapy Neuro Oncol 2016; 18 (suppl 6): vi148.
21. Robinson G.W., Rudneva V.A., Buchhal-ter I., Billups C.A., Waszak S.M., Smith K.S., et al. Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 2018 Jun; 19 (6): 768–84. Epub 2018 May 16.
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23. Gerber N.U., Juhnke B.-O., Mynarek M., Benesch M., Bertozzi A.I., Kortmann R.-D., et al. Treatment failure in young children with Desmoplastic Medulloblastoma (DMB)/Medulloblastoma with Extensive Nodularity (MBEN) treated according to the HIT protocols [abstract] Neuro Oncol 2016; 18 (suppl 3).
24. Ramaswamy V., Remke M., Bouffet E., Faria C.C., Perreault S., Cho Y.J., et al. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol 2013; 14 (12): 1200–7.
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Pediatric Hematology/Oncology and Immunopathology. 2018; 17: 43-49
Prognostic value of molecular, genetic and clinical characteristics of SHH group medulloblastoma
https://doi.org/10.24287/1726-1708-2018-17-3-43-49Abstract
SHH group of medulloblastoma is a heterogeneous tumor cohort. The neoplasms differ by biological characteristics as well as clinical features and prognosis of the disease. Purpose of the study is the analysis of clinical, molecular and genetic features for prognosis defining in patients with SHH group medulloblastoma. 28 patients with SHH group medulloblastomas were included in the study. The MB molecular group verification was performed in parallel by Nanostring gene expression profiling and immunohistochemical assessment of tumor samples. The detection of TP53 gene mutations was carried out with Sanger sequencing. The prognostic impact of the clinical, molecular and genetic factors of the disease was analyzed by calculating 5-years event-free survival (EFS). The median of follow up time achieved 38.9 months. All patients harboring the TP53 mutation (n = 3) had dismal outcome (two patients died from the progression of the disease, one patient has secondary tumor). Children from older age group (> 3 years) had more adverse events comparing to younger children (< 3 years): EFS 49.2 ± 31.3% vs. 78.8 ± 13.9%. The relapse of the disease occurred in 7 patients (25%). Notably, that in younger children the second line treatment was effective. The presence of TP53 mutations as well as age above 3 years are associated with poor prognosis in SHH group medulloblastomas. The novel molecular and genetics markers are needed for precise prognosis defining.
References
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10. Gibson P., Tong Y., Robinson G., Thompson M.C., Currle D.S., Eden C., et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 2010; 468: 1095–9.
11. Perreault S., Ramaswamy V., Achrol A.S., Chao K., Liu T.T., Shih D., et al. MRI surrogates for molecular subgroups of medulloblastoma. AJNR Am J Neuroradiol 2014; 35: 1263–9.
12. Tabori U., Baskin B., Shago M., Alon N., Taylor M.D., Ray P.N., et al. Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 2010; 28 (8): 1345–50.
13. 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.
14. Ramaswamy V., Remke M., Bouffet E., Baile S., Clifford S.C., Doz F., et al. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol 2016; 131: 821–31.
15. Rutkowski S., von Hoff K., Emser A., Zwiener I., Pietsch T., Figarella-Branger D., et al. Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 2010; 28 (33): 4961–8.
16. Grill J., Sainte-Rose C., Jouvet A., Gentet J.C., Lejars O., Frappaz D., et al. Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 2005; 6 (8): 573–80.
17. Leary S.E., Zhou T., Holmes E., Geyer J.R., Miller D.C. Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. Cancer 2011; 117 (14): 3262–26.
18. von Bueren A.O., von Hoff K., Pietsch T., Gerber N.U., Warmuth-Metz M., Deinlein F., et al. Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology. Neuro Oncol 2011; 13 (6): 669–79.
19. Abdelbaki M., Boue D., Finlay J., Kieran M. Desmoplastic medulloblastoma in young children: a management dilemma. Neuro Oncol 2018 Jul 5; 20 (8): 1026–33.
20. Upadhyaya S.A., Robinson G., Orr B., Onar-Thomas A., Billups C., Bowers D., et al. Outcomes for nonmetastatic Desmoplastic/Nodular infant Medul-loblastoma treated with reduced intensity chemotherapy and oral maintenance chemotherapy Neuro Oncol 2016; 18 (suppl 6): vi148.
21. Robinson G.W., Rudneva V.A., Buchhal-ter I., Billups C.A., Waszak S.M., Smith K.S., et al. Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 2018 Jun; 19 (6): 768–84. Epub 2018 May 16.
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23. Gerber N.U., Juhnke B.-O., Mynarek M., Benesch M., Bertozzi A.I., Kortmann R.-D., et al. Treatment failure in young children with Desmoplastic Medulloblastoma (DMB)/Medulloblastoma with Extensive Nodularity (MBEN) treated according to the HIT protocols [abstract] Neuro Oncol 2016; 18 (suppl 3).
24. Ramaswamy V., Remke M., Bouffet E., Faria C.C., Perreault S., Cho Y.J., et al. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol 2013; 14 (12): 1200–7.
25. Cavalli F.M. Remke M., Rampasek L., Peacock J., Shih D.J.H., Luu B., et al. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 2017; 31 (6): 737–54.
