nodgoРоссийский журнал детской гематологии и онкологии (РЖДГиО)Russian Journal of Pediatric Hematology and Oncology2311-12672413-5496LTD “Graphica”10.21682/2311-1267-2023-10-3-89-100nodgo-967Research ArticleКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯCLINICAL CASESCMMRD-ассоциированная эмбриональная рабдомиосаркома у ребенка. Клинический случай с обзором литературыCMMRD-associated embryonic rhabdomyosarcoma in a child. Clinical case with literature reviewhttps://orcid.org/0000-0001-8356-0625РодинаА. Д.RodinaA. D.

Анастасия Дмитриевна Родина - врач-детский онколог хирургического отделения № 1 (опухолей головы и шеи) НИИ детской онкологии и гематологии

 115522, Москва, Каширское шоссе, 23

Pediatric Oncologist Surgical Department No. 1 (Head and Neck Tumors) of the Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov

23 Kashirskoe Shosse, Moscow, 115522

dr.rodinaAD@yandex.ruhttps://orcid.org/0000-0002-8096-0874ПоляковВ. Г.PolyakovV. G.

академик РАН, д.м.н., профессор, советник директора и заведующий хирургическим отделением № 1 (опухолей головы и шеи) НИИ детской онкологии и гематологии им. акад. РАМН Л.А. Дурнова;  профессор кафедры оториноларингологии педиатрического факультета

115522, Москва, Каширское шоссе, 23

125993, Москва, ул. Баррикадная, 2/1, стр. 1

117997, Москва, ул. Островитянова, 1

Academician of RAS, Dr. of Sci. (Med.), Professor, Advisor to the Director and Head of the Surgical Department No. 1 (Head and Neck Tumors) of the Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Head of the Pediatric Oncology Department named after Academician L.A. Durnov at Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia, Professor of the Department of Otorhinolaryngology Faculty of Pediatrics at N.I. Pirogov Russian National Research Medical University,

23 Kashirskoe Shosse, Moscow, 115522

Bldg. 1, 2/1 Barrikadnaya St., Moscow, 125993

1 Ostrovityanova St., Moscow, 117997

vgp-04@mail.ruhttps://orcid.org/0000-0002-8476-7879КрыловА. С.KrylovA. S.

к.м.н., заведующий лабораторией радиоизотопной диагностики отдела радиоизотопной диагностики и терапии НИИ клинической и экспериментальной радиологии

115522, Москва, Каширское шоссе, 23

Cand. of Sci. (Med.), Head of the Laboratory of Radioisotope Diagnostics Department of Radioisotope Diagnostics and Therapy of the Research Institute of Clinical and Experimental Radiology

23 Kashirskoe Shosse, Moscow, 115522

krilovas@rambler.ruhttps://orcid.org/0000-0002-9705-1001СеменоваВ. В.SemenovaV. V.

врач-генетик НИИ детской онкологии и гематологии им. акад. РАМН Л.А. Дурнова

115522, Москва, Каширское шоссе, 23

ГСП-1, 119991, Москва, ул. Вавилова, 32

Geneticist Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Graduate Student of the Laboratory of Biological Microchips of Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

23 Kashirskoe Shosse, Moscow, 115522

32 Vavilova St., Moscow, 119991, GSP-1

sulpiridum@yandex.ruhttps://orcid.org/0000-0002-0442-5810КозловаВ. М.KozlovaV. M.

консультант поликлинического отделения НИИ детской онкологии и гематологии им. акад. РАМН Л.А. Дурнова

115522, Москва, Каширское шоссе, 23

Consultant of the Polyclinic Department Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov

23 Kashirskoe Shosse, Moscow, 115522

valentina-mk2011@yandex.ruhttps://orcid.org/0000-0002-2642-4202НаседкинаТ. В.NasedkinaT. V.

д.б.н., профессор, ведущий научный сотрудник лаборатории биологических микрочипов

ГСП-1, 119991, Москва, ул. Вавилова, 32

Dr. of Sci. (Biol.), Leading Researcher Laboratory of Biological Microchips of Engelhardt

32 Vavilova St., Moscow, 119991, GSP-1

tanased06@rambler.ruКашанинаА. Л.KashaninaA. L.

врач-рентгенолог детского отделения рентгенодиагностики консультативно-диагностического центра

115522, Москва, Каширское шоссе, 23

Radiologist of the Pediatric Radiology Department of Consultative and Diagnostic Center

23 Kashirskoe Shosse, Moscow, 115522

a.kashanina@yandex.ruhttps://orcid.org/0000-0003-3852-3969КозловН. А.KozlovN. A.

к.м.н., врач-патологоанатом патологоанатомического отделения отдела морфологической и молекулярно-генетической диагностики опухолей

115522, Москва, Каширское шоссе, 23

Cand. of Sci. (Med.), Pathologist Pathological Department of the Department of Morphological and Molecular-Genetic Diagnostics of Tumors

23 Kashirskoe Shosse, Moscow, 115522

newbox13@mail.ruhttps://orcid.org/0000-0003-3982-3066МигуноваВ. В.MigunovaV. V.

врач-ординатор хирургического отделения № 1 (опухолей головы и шеи) НИИ детской онкологии и гематологии

115522, Москва, Каширское шоссе, 23

Resident Physician Surgical Department No. 1 (Head and Neck Tumors) of the Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov

23 Kashirskoe Shosse, Moscow, 115522

migunovavaleria5@gmail.comhttps://orcid.org/0000-0001-5805-726XГорбуноваТ. В.GorbunovaT. V.

к.м.н., заместитель главного врача по медицинской части и старший научный сотрудник хирургического отделения № 1 (опухолей головы и шеи) НИИ детской онкологии и гематологии

115522, Москва, Каширское шоссе, 23

117997, Москва, ул. Островитянова, 1

 Cand. of Sci. (Med.), Deputy Chief Physician for Medical Affairs and Senior Researcher Surgical Department No. 1 (Head and Neck Tumors) of the Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Assistant of the Department of Otorhinolaryngology Faculty 

23 Kashirskoe Shosse, Moscow, 115522

1 Ostrovityanova St., Moscow, 117997

wasicsol@mail.ruФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава РоссииРоссияN.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of RussiaRussian FederationФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России; ФГБОУ ДПО РМАНПО Минздрава России; ФГАОУ ВО РНИМУ им. Н.И. Пирогова Минздрава РоссииРоссияN.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia; Russian Medical Academy of Continuous Professional Education, Ministry of Health of Russia; N.I. Pirogov Russian National Research Medical University, Ministry of Health of RussiaRussian FederationФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России; ФГБУН «Институт молекулярной биологии имени В.А. Энгельгардта Российской академии наук»РоссияN.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia; Engelhardt Institute of Molecular Biology, Russian Academy of SciencesRussian FederationФГБУН «Институт молекулярной биологии имени В.А. Энгельгардта Российской академии наук»РоссияEngelhardt Institute of Molecular Biology, Russian Academy of SciencesRussian FederationФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России; ФГАОУ ВО РНИМУ им. Н.И. Пирогова Минздрава РоссииРоссияN.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia; N.I. Pirogov Russian National Research Medical University, Ministry of Health of RussiaRussian Federation20233011202310389100Copyright © Родина А.Д., Поляков В.Г., Крылов А.С., Семенова В.В., Козлова В.М., Наседкина Т.В., Кашанина А.Л., Козлов Н.А., Мигунова В.В., Горбунова Т.В., 20232023Родина А.Д., Поляков В.Г., Крылов А.С., Семенова В.В., Козлова В.М., Наседкина Т.В., Кашанина А.Л., Козлов Н.А., Мигунова В.В., Горбунова Т.В.Rodina A.D., Polyakov V.G., Krylov A.S., Semenova V.V., Kozlova V.M., Nasedkina T.V., Kashanina A.L., Kozlov N.A., Migunova V.V., Gorbunova T.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nodgo.org/jour/article/view/967Введение

Введение. Наследственные нарушения в системе репарации ДНК могут привести к развитию злокачественных новообразований (ЗНО) в детском возрасте. Синдром дефицита в системе репарации неспаренных нуклеотидов ДНК (Constitutional mismatch repair deficiency syndrome, CMMRD) – очень редкое генетическое аутосомно-рецессивное заболевание, обусловленное гомозиготными мутациями в одном из 4 генов репарации неспаренных нуклеотидов (MLH1, MSH2, MSH6 и PMS2). Частота встречаемости – 0,0000001 у взрослого и детского населения. В мировой литературе на данный момент опубликовано около 150 наблюдений. Прогноз при синдроме CMMRD крайне неблагоприятен. Спектр опухолей, входящих в состав синдрома CMMRD, очень широк, включает в основном злокачественные опухоли головного мозга, опухоли пищеварительного тракта, гематологические ЗНО, эмбриональные опухоли, причем все они развиваются в детском возрасте.

Цель исследования – сообщить о случае развития CMMRD-ассоциированной эмбриональной рабдомиосаркомы (РМС) у ребенка 3 лет.

Выводы

Выводы. Обзор литературы и описанный нами клинический случай показывают, что РМС принадлежит к опухолевому спектру синдрома CMMRD. При иммуногистохимическом исследовании была выявлена изолированная потеря экспрессии гена PMS2. Учитывая клиническое течение синдрома CMMRD, рекомендовано тщательное изучение семейного анамнеза у пациентов с РМС, а также молекулярно-генетическое исследование, включающее в себя поиск герминальных мутаций в генах в системе репарации ДНК и оценку микросателлитной нестабильности в материале опухолевой ткани. Клинические симптомы синдрома CMMRD неспецифичны и зависят от морфологического варианта первичной опухоли. Отличительными молекулярно-генетическими признаками данного синдрома являются гомозиготные мутации с потерей функции зародышевой линии генов системы MMR (mismatch repair) (MLH1, MSH2, MSH6 или PMS2).

Introduction

Introduction. Hereditary disorders in the DNA repair system can lead to the development of malignant neoplasms in childhood. DNA constitutional mismatch repair deficiency syndrome (CMMRD) is a very rare genetic autosomal recessive disorder caused by homozygous mutations in one of the four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The frequency of occurrence is 0.0000001 of the adult and child population. For now about 150 observations have been published in the world literature. The prognosis for CMMRD syndrome is extremely unfavorable. The spectrum of tumors that make up the CMMRD syndrome is very wide, and includes mainly malignant brain tumors, tumors of the digestive tract, hematological malignancies, embryonic tumors, all of which develop in childhood.

The purpose of the study is to report a case of CMMRD-associated embryonic rhabdomyosarcoma in a 3-year-old child.

Conclusions

Conclusions. A review of the literature and the clinical case we have described show that rhabdomyosarcoma belongs to the tumor spectrum of the CMMRD syndrome. An immunohistochemical study revealed an isolated loss of PMS2 gene expression. Taking into account the clinical course of the CMMRD syndrome, a thorough study of the family history in patients with rhabdomyosarcoma is recommended, as well as a molecular genetic study, including the search for germinal mutations in genes in the DNA repair system and the assessment of microsatellite instability in the material of the tumor tissue. The clinical symptoms of CMMRD syndrome are nonspecific and depend on the morphological variant of the primary tumor. Distinctive molecular genetic features of this syndrome are: homozygous mutations with loss of function of the germline genes of the MMR system (mismatch repair) (MLH1, MSH2, MSH6 or PMS2).

дефицит репарации ДНКмутациидетирабдомиосаркомахимиотерапияDNA repair deficiencymutationschildrenrhabdomyosarcomachemotherapyReferencesJackson S.P., Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8. doi: 10.1038/nature08467.Jackson S.P., Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8. doi: 10.1038/nature08467.Khanna K.K., Jackson S.P. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001;27(3):247–54. doi: 10.1038/85798.Khanna K.K., Jackson S.P. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001;27(3):247–54. doi: 10.1038/85798.Hsieh P. Molecular mechanisms of DNA mismatch repair. Mutat Res. 2001;486(2):71–87. doi: 10.1016/s0921-8777(01)00088-x.Hsieh P. Molecular mechanisms of DNA mismatch repair. Mutat Res. 2001;486(2):71–87. doi: 10.1016/s0921-8777(01)00088-x.Pardo B., Gómez-González B., Aguilera A. DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci. 2009;66(6):1039–56. doi: 10.1007/s00018-009-8740-3.Pardo B., Gómez-González B., Aguilera A. DNA repair in mammalian cells: DNA double-strand break repair: how to fi x a broken relationship. Cell Mol Life Sci. 2009;66(6):1039–56. doi: 10.1007/s00018-009-8740-3.D’Andrea A.D. DNA Repair Pathways and Human Cancer. The Molecular Basis of Cancer: 4th Edition, 2014. Pp. 47–66.e2. doi: 10.1016/B978-1-4557-4066-6.00004-4.D’Andrea A.D. DNA Repair Pathways and Human Cancer. The Molecular Basis of Cancer: 4th Edition, 2014. Pp. 47–66.e2. doi: 10.1016/B978-1-4557-4066-6.00004-4.Hause R.J., Pritchard C.C., Shendure J., Salipante S.J. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22(11):1342–50. doi: 10.1038/nm.4191.Hause R.J., Pritchard C.C., Shendure J., Salipante S.J. Classifi cation and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22(11):1342–50. doi: 10.1038/nm.4191.Chang S.C., Lan Y.T., Lin P.C., Yang S.H., Lin C.H., Liang W.Y., Chen W.S., Jiang J.K., Lin J.K. Patterns of germline and somatic mutations in 16 genes associated with mismatch repair function or containing tandem repeat sequences. Cancer Med. 2020;9(2):476–86. doi: 10.1002/cam4.2702.Chang S.C., Lan Y.T., Lin P.C., Yang S.H., Lin C.H., Liang W.Y., Chen W.S., Jiang J.K., Lin J.K. Patterns of germline and somatic mutations in 16 genes associated with mismatch repair function or containing tandem repeat sequences. Cancer Med. 2020;9(2):476–86. doi: 10.1002/cam4.2702.Tamura K., Kaneda M., Futagawa M., Takeshita M., Kim S., Nakama M., Kawashita N., Tatsumi-Miyajima J. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin Oncol. 2019;24(9):999–1011. doi: 10.1007/s10147-019-01494-y.Tamura K., Kaneda M., Futagawa M., Takeshita M., Kim S., Nakama M., Kawashita N., Tatsumi-Miyajima J. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin Oncol. 2019;24(9):999–1011. doi: 10.1007/s10147-019-01494-y.Boland P.M., Yurgelun M.B., Boland C.R. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J Clin. 2018;68(3):217–31. doi: 10.3322/caac.21448.Boland P.M., Yurgelun M.B., Boland C.R. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J Clin. 2018;68(3):217–31. doi: 10.3322/caac.21448.Adam R., Spier I., Zhao B., Kloth M., Marquez J., Hinrichsen I., Kirfel J., Tafazzoli A., Horpaopan S., Uhlhaas S., Stienen D., Friedrichs N., Altmüller J., Laner A., Holzapfel S., Peters S., Kayser K., Thiele H., Holinski-Feder E., Marra G., Kristiansen G., Nöthen M.M., Büttner R., Möslein G., Betz R.C., Brieger A., Lifton R.P., Aretz S. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am J Hum Genet. 2016;99(2):337–51. doi: 10.1016/j.ajhg.2016.06.015.Adam R., Spier I., Zhao B., Kloth M., Marquez J., Hinrichsen I., Kirfel J., Tafazzoli A., Horpaopan S., Uhlhaas S., Stienen D., Friedrichs N., Altmüller J., Laner A., Holzapfel S., Peters S., Kayser K., Thiele H., Holinski-Feder E., Marra G., Kristiansen G., Nöthen M.M., Büttner R., Möslein G., Betz R.C., Brieger A., Lifton R.P., Aretz S. Exome Sequencing Identifi es Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am J Hum Genet. 2016;99(2):337–51. doi: 10.1016/j.ajhg.2016.06.015.Lynch H.T., Lynch P.M., Pester J., Fusaro R.M. The cancer family syndrome. Rare cutaneous phenotypic linkage of Torre’s syndrome. Arch Intern Med. 1981;141(5):607–11. PMID: 7224741.Lynch H.T., Lynch P.M., Pester J., Fusaro R.M. The cancer family syndrome. Rare cutaneous phenotypic linkage of Torre’s syndrome. Arch Intern Med. 1981;141(5):607–11. PMID: 7224741.Barana D., van der Klift H., Wijnen J., Longa E.D., Radice P., Cetto G.L., Fodde R., Oliani C. Spectrum of genetic alterations in Muir–Torre syndrome is the same as in HNPCC. Am J Med Genet A. 2004;125A(3):318–9. doi: 10.1002/ajmg.a.20523.Barana D., van der Klift H., Wijnen J., Longa E.D., Radice P., Cetto G.L., Fodde R., Oliani C. Spectrum of genetic alterations in Muir–Torre syndrome is the same as in HNPCC. Am J Med Genet A. 2004;125A(3):318–9. doi: 10.1002/ajmg.a.20523.Bakry D., Aronson M., Durno C., Rimawi H., Farah R., Alharbi Q.K., Alharbi M., Shamvil A., Ben-Shachar S., Mistry M., Constantini S., Dvir R., Qaddoumi I., Gallinger S., Lerner-Ellis J., Pollett A., Stephens D., Kelies S., Chao E., Malkin D., Bouffet E., Hawkins C., Tabori U. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer. 2014;50(5):987–96. doi: 10.1016/j.ejca.2013.12.005.Bakry D., Aronson M., Durno C., Rimawi H., Farah R., Alharbi Q.K., Alharbi M., Shamvil A., Ben-Shachar S., Mistry M., Constantini S., Dvir R., Qaddoumi I., Gallinger S., Lerner-Ellis J., Pollett A., Stephens D., Kelies S., Chao E., Malkin D., Bouff et E., Hawkins C., Tabori U. Genetic and clinical determinants of constitutional mismatch repair defi ciency syndrome: report from the constitutional mismatch repair defi ciency consortium. Eur J Cancer. 2014;50(5):987–96. doi: 10.1016/j.ejca.2013.12.005.Suerink M., Wimmer K., Brugieres L., Colas C., Gallon R., Ripperger T., Benusiglio P.R., Bleiker E.M.A., Ghorbanoghli Z., Goldberg Y., Hardwick J.C.H., Kloor M., le Mentec M., Muleris M., Pineda M., Ruiz-Ponte C., Vasen H.F.A. Report of the fifth meeting of the European Consortium “Care for CMMRD” (C4CMMRD), Leiden, The Netherlands, July 6th 2019. Fam Cancer. 2021;20(1):67–73. doi: 10.1007/s10689-020-00194-1.Suerink M., Wimmer K., Brugieres L., Colas C., Gallon R., Ripperger T., Benusiglio P.R., Bleiker E.M.A., Ghorbanoghli Z., Goldberg Y., Hardwick J.C.H., Kloor M., le Mentec M., Muleris M., Pineda M., Ruiz-Ponte C., Vasen H.F.A. Report of the fi fth meeting of the European Consortium “Care for CMMRD” (C4CMMRD), Leiden, The Netherlands, July 6th 2019. Fam Cancer. 2021;20(1):67–73. doi: 10.1007/s10689-020-00194-1.Tabori U., Hansford J.R., Achatz M.I., Kratz C.P., Plon S.E., Frebourg T., Brugières L. Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood. Clin Cancer Res. 2017;23(11):e32–e37. doi: 10.1158/1078-0432.CCR-17-0574.Tabori U., Hansford J.R., Achatz M.I., Kratz C.P., Plon S.E., Frebourg T., Brugières L. Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Defi ciency in Childhood. Clin Cancer Res. 2017;23(11):e32–e37. doi: 10.1158/1078-0432.CCR-17-0574.Martin-Giacalone B.A., Weinstein P.A., Plon S.E., Lupo P.J. Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility. J Clin Med. 2021;10(9):2028. doi: 10.3390/jcm10092028.Martin-Giacalone B.A., Weinstein P.A., Plon S.E., Lupo P.J. Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility. J Clin Med. 2021;10(9):2028. doi: 10.3390/jcm10092028.Silva F.C., Valentin M.D., Ferreira F.O., Carraro D.M., Rossi B.M. Mismatch repair genes in Lynch syndrome: a review. Sao Paulo Med J. 2009;127(1):46–51. doi: 10.1590/s1516-31802009000100010.Silva F.C., Valentin M.D., Ferreira F.O., Carraro D.M., Rossi B.M. Mismatch repair genes in Lynch syndrome: a review. Sao Paulo Med J. 2009;127(1):46–51. doi: 10.1590/s1516-31802009000100010.Wimmer K., Kratz C.P., Vasen H.F., Caron O., Colas C., Entz-Werle N., Gerdes A.M., Goldberg Y., Ilencikova D., Muleris M., Duval A., Lavoine N., Ruiz-Ponte C., Slavc I., Burkhardt B., Brugieres L.; EU-Consortium Cafe for CMMRD (C4CMMRD). Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium “cafe for CMMRD” (C4CMMRD). J Med Genet. 2014;51(6):355–65. doi: 10.1136/jmedgenet-2014-102284.Wimmer K., Kratz C.P., Vasen H.F., Caron O., Colas C., Entz-Werle N., Gerdes A.M., Goldberg Y., Ilencikova D., Muleris M., Duval A., Lavoine N., Ruiz-Ponte C., Slavc I., Burkhardt B., Brugieres L.; EU-Consortium Cafe for CMMRD (C4CMMRD). Diagnostic criteria for constitutional mismatch repair defi ciency syndrome: suggestions of the European consortium “cafe for CMMRD” (C4CMMRD). J Med Genet. 2014;51(6):355–65. doi: 10.1136/jmedgenet-2014-102284.Bailly C. Topoisomerase I poisons and suppressors as anticancer drugs. Curr Med Chem. 2000;7(1):39–58. doi: 10.2174/0929867003375489.Bailly C. Topoisomerase I poisons and suppressors as anticancer drugs. Curr Med Chem. 2000;7(1):39–58. doi: 10.2174/0929867003375489.Nitiss J.L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009;9(5):338–50. doi: 10.1038/nrc2607.Nitiss J.L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009;9(5):338–50. doi: 10.1038/nrc2607.Aronson M., Colas C., Shuen A., Hampel H., Foulkes W.D., Baris Feldman H., Goldberg Y., Muleris M., Wolfe Schneider K., McGee R.B., Jasperson K., Rangaswami A., Brugieres L., Tabori U. Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group. J Med Genet. 2022;59(4):318–27. doi: 10.1136/jmedgenet-2020-107627.Aronson M., Colas C., Shuen A., Hampel H., Foulkes W.D., Baris Feldman H., Goldberg Y., Muleris M., Wolfe Schneider K., McGee R.B., Jasperson K., Rangaswami A., Brugieres L., Tabori U. Diagnostic criteria for constitutional mismatch repair defi ciency (CMMRD): recommendations from the international consensus working group. J Med Genet. 2022;59(4):318–27. doi: 10.1136/jmedgenet-2020-107627.Cronin M., Ross J.S. Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology. Biomark Med. 2011;5(3):293–305. doi: 10.2217/bmm.11.37.Cronin M., Ross J.S. Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology. Biomark Med. 2011;5(3):293–305. doi: 10.2217/bmm.11.37.Rizzo J.M., Buck M.J. Key principles and clinical applications of “next-generation” DNA sequencing. Cancer Prev Res (Phila). 2012;5(7):887–900. doi: 10.1158/1940-6207.CAPR-11-0432.Rizzo J.M., Buck M.J. Key principles and clinical applications of “next-generation” DNA sequencing. Cancer Prev Res (Phila). 2012;5(7):887–900. doi: 10.1158/1940-6207.CAPR-11-0432.Kratz C.P., Holter S., Etzler J., Lauten M., Pollett A., Niemeyer C.M., Gallinger S., Wimmer K. Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome. J Med Genet. 2009;46(6):418–20. doi: 10.1136/jmg.2008.064212.Kratz C.P., Holter S., Etzler J., Lauten M., Pollett A., Niemeyer C.M., Gallinger S., Wimmer K. Rhabdomyosarcoma in patients with constitutional mismatch-repair-defi ciency syndrome. J Med Genet. 2009;46(6):418–20. doi: 10.1136/jmg.2008.064212.

The authors declare that there are no conflicts of interest present.