Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2020; 19: 82-87
Распространенность аномалий гена FOXO1 в группе круглоклеточных рабдомиосарком с альвеолярной морфологией
https://doi.org/10.24287/1726-1708-2020-19-4-82-87Аннотация
Рабдомиосаркомы (РМС) – группа злокачественных опухолей мягких тканей, как считалось, преимущественно детского возраста. Альвеолярная РМС (аРМС) является вторым по частоте встречаемости вариантом РМС. В подавляющем большинстве случаев при аРМС обнаруживается транслокация гена FOXO1. Такие опухоли агрессивны, рано метастазируют и ассоциированы с худшим прогнозом для пациента. Однако часть случаев аРМС относятся к РМС без классических хромосомных перестроек. Данные опухоли также имеют альвеолярную морфологию, но в неопластических клетках отсутствует транслокация гена FOXO1. Эти неперестроенные круглоклеточные РМС клинически ведут себя иначе и имеют более благоприятный прогноз. Цель работы: провести оценку частоты встречаемости перестроек гена FOXO1 в группе круглоклеточных РМС с альвеолярной морфологией. Исследуемую группу составили 250 образцов опухолевой ткани пациентов с РМС. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. Цитогенетическое исследование проводилось методом флуоресцентной гибридизации in situ с локус-специфичным зондом FOXO1 (13q14). Выявление химерных транскриптов PAX3-FOXO1 (COSF247) и PAX7-FOXO1 (COSF287) проводилось с помощью полимеразной цепной реакции (ПЦР) в режиме реального времени. В исследуемой группе 1 (аРМС) перестройка PAX3/7-FOXO1 была выявлена в 44% случаев, в 32% была обнаружена сочетанная перестройка с амплификацией 3’ конца гена FOXO1. В 1 случае выявлена амплификация 3’ конца гена FOXO1 без перестройки, данный образец был отправлен на дополнительное исследование методом ПЦР, в результате которого был обнаружен химерный транскрипт PAX3-FOXO1. В 22% случаев не было выявлено никаких изменений. В группе 2 (эмбриональные РМС) в 100% случаев не было выявлено перестройки гена FOXO1. Группа круглоклеточных РМС с генетической точки зрения является неоднородной и представлена 3 вариантами генетических событий, определяющих прогноз течения болезни. В то же время в группе РМС с неальвеолярной морфологией аномалии гена FOXO1 не встречаются.
Список литературы
1. Egas-Bejar D., Huh W.W. Rhabdomyosarcoma in adolescent and young adult patients: current perspectives. Adolesc Health Med Ther 2014; 5: 115–25. DOI: 10.2147/AHMT.S44582
2. Kumar A., Singh M., Sharma M.C., Bakshi S., Sharma B.S. Pediatric sclerosing rhabdomyosarcomas: a review. ISRN Oncol 2014; 2014: 640195. DOI: 10.1155/2014/640195
3. McDowell H.P. Update on childhood rhabdomyosarcoma. Arch Dis Child 2003; 88: 354–7. DOI: 10.1136/adc.88.4.354
4. O'Neill J.P., Bilsky M.H., Kraus D. Head and neck sarcomas: epidemiology, pathology, and management. Neurosurg Clin North Am 2013; 24: 67–8. DOI: 10.1016/j.nec.2012.08.010
5. Ray A., Huh W.W. Current state-of-theart systemic therapy for pediatric soft tissue sarcomas. Curr Oncol Rep 2012; 14: 311–9 DOI: 10.1007/s11912-012-0243-y
6. Yang L., Takimoto T., Fujimoto J. Prognostic model for predicting overall survival in children and adolescents with rhabdomyosarcoma. BMC Cancer 2014; 14: 654. DOI: 10.1186/1471-2407-14-654
7. Kuda M., Kohashi K., Yamada Y., Maekawa A., Kinoshita Y., Nakatsura T., et al. FOXM1 expression in rhabdomyosarcoma: a novel prognostic factor and therapeutical target. Tumour Biol 2016; 37: 5213–23. DOI: 10.1007/s13277-015-4351-9
8. Ji J., Eng C., Hemminki K. Familial risk for soft tissue tumors: a nation-wide epidemiological study from Sweden. J Cancer Res Clin Oncol 2008; 134: 617–24. DOI: 10.1007/s00432-007-0327-5
9. Jones A.E., Albano E.A., Lovell M.A., Hunger S.P. Metastatic alveolar rhabdomyosarcoma in multiple endocrine neoplasia type 2A. Pediatr Blood Cancer 2010; 55: 1213–6. DOI: 10.1002/pbc.22591
10. Li F.P., Fraumeni J.F. Jr. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 1969; 43: 1365–73. DOI: 10.1093/jnci/43.6.1365
11. Samuel D.P., Tsokos M., DeBaun M.R. Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol 1999; 32: 38–43. DOI: 10.1002/(SICI)1096-911X(199901)32:1<38::AIDMPO8>3.0.CO;2-H
12. Alaggio R., Zhang L., Sung Y.S., Huang S.C., Chen C.L., Bisogno G., et al. A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol 2016; 40: 224–35. DOI: 10.1097/PAS.0000000000000538
13. Stock N., Chibon F., Binh M.B., Terrier P., Michels J.J., Valo I., et al. Adulttype rhabdomyosarcoma: analysis of 57 cases with clinicopathologic description, identification of 3 morphologic patterns and prognosis. Am J Surg Pathol 2009; 33: 1850–9. DOI: 10. 1097/PAS.0b013e3181be6209
14. Agaram N.P., LaQuaglia M.P., Alaggio R., Zhang L., Fujisawa Y., Ladanyi M., et al. MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age A reappraisal for molecular classification and risk stratification. Mod Pathol 2018; 32: 27–36. DOI: 10.1038/s41379-018-0120-9
15. WHO Classification of Tumours of Soft Tissue and Bone. (5th ed.). Lyon: IARC Press; 2019.
16. Parham D.M., Barr F.G. Classification of rhabdomyosarcoma and its molecular basis. Adv Anat Pathol 2013; 20: 387–97. DOI: 10.1097/PAP.0b013e3182a92d0d
17. Xia S.J., Pressey J.G., Barr F.G. Molecular pathogenesis of rhabdomyosarcoma. Biol Ther 2002; 1: 97–104. DOI: 10.4161/cbt.51
18. Polito P., Cin P.D., Debiec-Rychter M., Hagemeijer A. Human solid tumors: Cytogenetic techniques. In: Methods in Molecular Biology, vol. 220: Cancer Cytogenetics: Methods and Protocols. Totowa, NJ: Humana Press; 2003. Рр.135–150. DOI: 10.1385/1-59259-363-1:135
19. Bridge J.A., Liu J., Qualman S.J., Suijkerbuijk R., Wenger G., Zhang J., et al. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer 2002; 33: 310–21. DOI: 10.1002/gcc.10026
20. Goldstein M., Meller I., Issakov J., Orr-Urtreger A. Novel genes implicated in embryonal, alveolar, and pleomorphic rhabdomyosarcoma: a cytogenetic and molecular analysis of primary tumors. Neoplasia 2006; 8: 332–43. DOI: 10.1593/neo.05829
21. Missiaglia E., Selfe J., Hamdi M., Williamson D., Schaaf G., Fang C., et al. Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: an approach to identify candidate genes involved in tumor development. Genes Chromosomes Cancer 2009; 48: 455–67. DOI: 10.1002/gcc.20655
22. Anderson J., Gordon T., McManus A., Mapp T., Gould S., Kelsey A, et al. Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: A reproducible predictor of outcome? Br J Cancer 2001; 85: 831–5. DOI: 10.1054/ bjoc.2001.2008
23. Sorensen P.H., Lynch J.C., Qualman S.J., Tirabosco R., Lim J.F., Maurer H.M., et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: A report from the Children's Oncology Group J Clin Oncol 2002; 20: 2672–9. DOI: 10.1200/JCO.2002.03.137
24. Helman L.J., Meltzer P. Mechanisms of sarcoma development. Nat Rev Cancer 2003; 3: 685–94. DOI: 10.1038/nrc1168.
25. Williamson D., Missiaglia E., de Reyniès A., Pierron G., Thuille B., Palenzuela G., et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 2010; 28 (13): 2151–8. DOI: 10.1200/JCO.2009.26.381
26. ISCN 2016 An international systeme for human cytogenetic nomenclature. McGowan-Jordan J., Simons A., Schmid M. (eds). Karger S., Basel; 2016.
27. Leiner J., Le Loarer F. The current landscape of rhabdomyosarcomas: an update. Virchows Arch 2020; 476: 97–108. DOI: 10.1007/s00428-019-02676-9
28. Ioannou M., Perivoliotis K., Zaharos N.-M., Tsanakas A., Tepetes K., Koukoulis G. Alveolar rhabdomyosarcoma with unusual cytogenetic findings: one more case and review of the literature. Oxf Med Case Reports 2019; 2019 (10): omz107. DOI: 10.1093/omcr/omz107
29. Duan F., Smith L.M., Gustafson D.M., Zhang C., Dunlevy M.J., Gastier-Foster J.M., Barr FG. Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group. Genes Chromosomes Cancer. 2012; 51 (7): 662–74. DOI: 10.1002/gcc.21953
30. Gordon A.T., Brinkschmidt C., Anderson J., Coleman N., Dockhorn-Dworniczak B., Pritchard-Jones K., Shipley J. A novel and consistent amplicon at 13q31 associated with alveolar rhabdomyosarcoma. Genes Chromosomes Cancer 2000; 28 (2): 220– 6. DOI: 10.1016/S0165-4608(02)00631-3
31. Bridge J.A., Liu J., Qualman S.J., Suijkerbuijk R., Wenger G., Zhang J., et al. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer. 2002; 33 (3): 310–21. DOI: 10.1002/gcc.10026
Pediatric Hematology/Oncology and Immunopathology. 2020; 19: 82-87
Prevalence of FOXO1 gene abnormalities in a group of round-cell rhabdomyosarcomas with alveolar morphology
https://doi.org/10.24287/1726-1708-2020-19-4-82-87Abstract
Rhabdomyosarcomas (RMS) are group of soft tissue malignant tumours predominantly childhood. Alveolar rhabdomyosarcoma (aRMS) is the second most common variant of RMS. The majority of aRMSs display a translocations of FOXO1 gene. Such tumours are aggressive, metastasize early and are associated with a worse prognosis for the patient. However, some aRMS cases are rhabdomyosarcomas without classic chromosomal rearrangements. These tumors also have alveolar morphology, but neoplastic cells lack the FOXO1 gene translocation. Such fusion-negative round-cell RMSs behave clinically differently and have a better prognosis. The aim of the present study was to assess the prevalence of FOXO1 gene rearrangements in the group of round cell rhabdomyosarcomas with alveolar morphology. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The study group consisted of 250 formalin-fixed paraffin-embedded samples from patients with RMS. The cytogenetic study was performed by fluorescence in situ hybridization with a locus-specific identifier (LSI) for FOXO1 (13q14). The PAX3-FOXO1 (COSF247) and PAX7-FOXO1 (COSF287) fusion transcripts was detected by RT-PCR. In the study group 1 (аRMS), the rearrangement of PAX3/7-FOXO1 was detected in 44% of cases, in 32% of cases was detected a combined rearrangement with amplification of the 3' FOXO1. In one case, the amplification of the 3' end of the FOXO1 gene was detected without rearrangement; this sample was sent for additional PCR study, as a result of which the chimeric PAX3-FOXO1 transcript was detected. In 22% cases cytogenetic abnormalities were not found. has not been identified. In group 2 (embryonal RMS) we did not detect translocation. The group of round-cell PMCs is heterogeneous and is represented by three variants of genetic events that determine the disease prognosis. At the same time, FOXO1 gene abnormalities are not found in the RMS group with non-alveolar morphology.
References
1. Egas-Bejar D., Huh W.W. Rhabdomyosarcoma in adolescent and young adult patients: current perspectives. Adolesc Health Med Ther 2014; 5: 115–25. DOI: 10.2147/AHMT.S44582
2. Kumar A., Singh M., Sharma M.C., Bakshi S., Sharma B.S. Pediatric sclerosing rhabdomyosarcomas: a review. ISRN Oncol 2014; 2014: 640195. DOI: 10.1155/2014/640195
3. McDowell H.P. Update on childhood rhabdomyosarcoma. Arch Dis Child 2003; 88: 354–7. DOI: 10.1136/adc.88.4.354
4. O'Neill J.P., Bilsky M.H., Kraus D. Head and neck sarcomas: epidemiology, pathology, and management. Neurosurg Clin North Am 2013; 24: 67–8. DOI: 10.1016/j.nec.2012.08.010
5. Ray A., Huh W.W. Current state-of-theart systemic therapy for pediatric soft tissue sarcomas. Curr Oncol Rep 2012; 14: 311–9 DOI: 10.1007/s11912-012-0243-y
6. Yang L., Takimoto T., Fujimoto J. Prognostic model for predicting overall survival in children and adolescents with rhabdomyosarcoma. BMC Cancer 2014; 14: 654. DOI: 10.1186/1471-2407-14-654
7. Kuda M., Kohashi K., Yamada Y., Maekawa A., Kinoshita Y., Nakatsura T., et al. FOXM1 expression in rhabdomyosarcoma: a novel prognostic factor and therapeutical target. Tumour Biol 2016; 37: 5213–23. DOI: 10.1007/s13277-015-4351-9
8. Ji J., Eng C., Hemminki K. Familial risk for soft tissue tumors: a nation-wide epidemiological study from Sweden. J Cancer Res Clin Oncol 2008; 134: 617–24. DOI: 10.1007/s00432-007-0327-5
9. Jones A.E., Albano E.A., Lovell M.A., Hunger S.P. Metastatic alveolar rhabdomyosarcoma in multiple endocrine neoplasia type 2A. Pediatr Blood Cancer 2010; 55: 1213–6. DOI: 10.1002/pbc.22591
10. Li F.P., Fraumeni J.F. Jr. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 1969; 43: 1365–73. DOI: 10.1093/jnci/43.6.1365
11. Samuel D.P., Tsokos M., DeBaun M.R. Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol 1999; 32: 38–43. DOI: 10.1002/(SICI)1096-911X(199901)32:1<38::AIDMPO8>3.0.CO;2-H
12. Alaggio R., Zhang L., Sung Y.S., Huang S.C., Chen C.L., Bisogno G., et al. A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol 2016; 40: 224–35. DOI: 10.1097/PAS.0000000000000538
13. Stock N., Chibon F., Binh M.B., Terrier P., Michels J.J., Valo I., et al. Adulttype rhabdomyosarcoma: analysis of 57 cases with clinicopathologic description, identification of 3 morphologic patterns and prognosis. Am J Surg Pathol 2009; 33: 1850–9. DOI: 10. 1097/PAS.0b013e3181be6209
14. Agaram N.P., LaQuaglia M.P., Alaggio R., Zhang L., Fujisawa Y., Ladanyi M., et al. MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age A reappraisal for molecular classification and risk stratification. Mod Pathol 2018; 32: 27–36. DOI: 10.1038/s41379-018-0120-9
15. WHO Classification of Tumours of Soft Tissue and Bone. (5th ed.). Lyon: IARC Press; 2019.
16. Parham D.M., Barr F.G. Classification of rhabdomyosarcoma and its molecular basis. Adv Anat Pathol 2013; 20: 387–97. DOI: 10.1097/PAP.0b013e3182a92d0d
17. Xia S.J., Pressey J.G., Barr F.G. Molecular pathogenesis of rhabdomyosarcoma. Biol Ther 2002; 1: 97–104. DOI: 10.4161/cbt.51
18. Polito P., Cin P.D., Debiec-Rychter M., Hagemeijer A. Human solid tumors: Cytogenetic techniques. In: Methods in Molecular Biology, vol. 220: Cancer Cytogenetics: Methods and Protocols. Totowa, NJ: Humana Press; 2003. Rr.135–150. DOI: 10.1385/1-59259-363-1:135
19. Bridge J.A., Liu J., Qualman S.J., Suijkerbuijk R., Wenger G., Zhang J., et al. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer 2002; 33: 310–21. DOI: 10.1002/gcc.10026
20. Goldstein M., Meller I., Issakov J., Orr-Urtreger A. Novel genes implicated in embryonal, alveolar, and pleomorphic rhabdomyosarcoma: a cytogenetic and molecular analysis of primary tumors. Neoplasia 2006; 8: 332–43. DOI: 10.1593/neo.05829
21. Missiaglia E., Selfe J., Hamdi M., Williamson D., Schaaf G., Fang C., et al. Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: an approach to identify candidate genes involved in tumor development. Genes Chromosomes Cancer 2009; 48: 455–67. DOI: 10.1002/gcc.20655
22. Anderson J., Gordon T., McManus A., Mapp T., Gould S., Kelsey A, et al. Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: A reproducible predictor of outcome? Br J Cancer 2001; 85: 831–5. DOI: 10.1054/ bjoc.2001.2008
23. Sorensen P.H., Lynch J.C., Qualman S.J., Tirabosco R., Lim J.F., Maurer H.M., et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: A report from the Children's Oncology Group J Clin Oncol 2002; 20: 2672–9. DOI: 10.1200/JCO.2002.03.137
24. Helman L.J., Meltzer P. Mechanisms of sarcoma development. Nat Rev Cancer 2003; 3: 685–94. DOI: 10.1038/nrc1168.
25. Williamson D., Missiaglia E., de Reyniès A., Pierron G., Thuille B., Palenzuela G., et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 2010; 28 (13): 2151–8. DOI: 10.1200/JCO.2009.26.381
26. ISCN 2016 An international systeme for human cytogenetic nomenclature. McGowan-Jordan J., Simons A., Schmid M. (eds). Karger S., Basel; 2016.
27. Leiner J., Le Loarer F. The current landscape of rhabdomyosarcomas: an update. Virchows Arch 2020; 476: 97–108. DOI: 10.1007/s00428-019-02676-9
28. Ioannou M., Perivoliotis K., Zaharos N.-M., Tsanakas A., Tepetes K., Koukoulis G. Alveolar rhabdomyosarcoma with unusual cytogenetic findings: one more case and review of the literature. Oxf Med Case Reports 2019; 2019 (10): omz107. DOI: 10.1093/omcr/omz107
29. Duan F., Smith L.M., Gustafson D.M., Zhang C., Dunlevy M.J., Gastier-Foster J.M., Barr FG. Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group. Genes Chromosomes Cancer. 2012; 51 (7): 662–74. DOI: 10.1002/gcc.21953
30. Gordon A.T., Brinkschmidt C., Anderson J., Coleman N., Dockhorn-Dworniczak B., Pritchard-Jones K., Shipley J. A novel and consistent amplicon at 13q31 associated with alveolar rhabdomyosarcoma. Genes Chromosomes Cancer 2000; 28 (2): 220– 6. DOI: 10.1016/S0165-4608(02)00631-3
31. Bridge J.A., Liu J., Qualman S.J., Suijkerbuijk R., Wenger G., Zhang J., et al. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer. 2002; 33 (3): 310–21. DOI: 10.1002/gcc.10026
