Supportive Therapy in OncologySupportive Therapy in OncologyПоддерживающая терапия в онкологии3034-24733034-3178Publishing House ABV Press5010.17650/3034-2473-2025-2-1-21-29REVIEWSОБЗОРНЫЕ СТАТЬИHereditary diseases and tumors in childrenНаследственные болезни и опухоли у детейhttps://orcid.org/0000-0003-0390-8498KulyovaS. A.КулеваС. А.
Russian Federation

Svetlana Aleksandrovna Kulyova 

68 Leningradskaya St., Pesochnyy, Saint Petersburg 197758

2 Litovskaya St., Saint Petersburg 194100

Светлана Александровна Кулева

97758 Санкт-Петербург, п. Песочный, ул. Ленинградская, 68 

194100 Санкт-Петербург, ул. Литовская, 2 

Kulevadoc@yandex.ruhttps://orcid.org/0000-0001-7195-6307RyazankinaA. A.РязанкинаА. А.
Russian Federation

68 Leningradskaya St., Pesochnyy, Saint Petersburg 197758

41 Kirochnaya St., Saint Petersburg 191015 

197758 Санкт-Петербург, п. Песочный, ул. Ленинградская, 68 

191015 Санкт-Петербург, ул. Кирочная, 41

https://orcid.org/0009-0000-1190-7220VasilevaM. М.ВасильеваМ. М.
Russian Federation

2 Litovskaya St., Saint Petersburg 194100 

194100 Санкт-Петербург, ул. Литовская, 2 

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Петрова» Минздрава РоссииSaint Petersburg State Pediatric Medical University, Ministry of Health of RussiaФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава РоссииI.I. Mechnikov North-Western State Medical University, Ministry of Health of RussiaФГБОУ ВО «Северо-Западный государственный медицинский университет им. И.И. Мечникова» Минздрава России150420252121290704202507042025Copyright ©; 2025, Kulyova S.A., Ryazankina A.A., Vasileva M.М.Copyright ©; 2025, Кулева С.А., Рязанкина А.А., Васильева М.М.2025Kulyova S.A., Ryazankina A.A., Vasileva M.М.Кулева С.А., Рязанкина А.А., Васильева М.М.https://creativecommons.org/licenses/by/4.0https://stio.abvpress.ru/jour/article/view/50

In recent years, our ability to use genome-wide analyses, including whole-genome and whole-exome sequencing, to determine the genetic basis of pediatric tumors has expanded significantly. In particular, exome sequencing has contributed the evidence that approximately 10 % of children and adolescents with tumors have genetic variant mutations associated with cancer susceptibility.In this review, we present a list of some genetic variations predisposing children to solid tumors.

За последние годы для определения генетической основы опухолей у детей наши возможности по использованию анализа в масштабе генома, включая генотипирование высокой плотности и секвенирование экзома и генома, значительно расширились. В частности, экзомное секвенирование способствовало получению доказательств того, что около 10 % детей и подростков с опухолями имеют генетические варианты мутаций, связанные с предрасположенностью к раку.В обзоре представлен перечень некоторых генетических вариаций, предрасполагающих к солидным опухолям у детей.

childrenhereditary diseasetumorдетинаследственная болезньопухольSweet-Cordero E.A., Biegel J.A. The genomic landscape of pediatric cancers: implications for diagnosis and treatment. Science 2019;363(6432):1170–5. DOI: 10.1126/science.aaw3535Gröbner S.N., Worst B.C., Weischenfeldt J. et al. The landscape of genomic alterations across childhood cancers [published correction appears in Nature 2018;559(7714):E10]. Nature 2018;555(7696):321–7. DOI: 10.1038/nature25480Zhang J., Walsh M.F., Wu G. et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med 2015;373(24):2336–46. DOI: 10.1056/NEJMoa1508054Akhavanfard S., Padmanabhan R., Yehia L. et al. Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors. Nat Commun 2020;11(1):2206. DOI: 10.1038/s41467-020-16067-1Postema F.A.M., Hopman S.M.J., Hennekam R.C., Merks J.H.M. Consequences of diagnosing a tumor predisposition syndrome in children with cancer: a literature review. Pediatr Blood Cancer 2018;65(1). DOI: 10.1002/pbc.26718Bamshad M.J., Ng S.B., Bigham A.W. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011;12(11):745–55. DOI: 10.1038/nrg3031Ballinger M.L., Goode D.L., Ray-Coquard I. et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. Lancet Oncol 2016;17(9):1261–71. DOI: 10.1016/S1470-2045(16)30147-4Musa J., Grünewald T.G.P. Interaction between somatic mutations and germline variants contributes to clinical heterogeneity in cancer. Mol Cell Oncol 2020;7(1):1682924. DOI: 10.1080/23723556.2019.1682924Knudson A.G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68(4):820–3. DOI: 10.1073/pnas.68.4.820Brodeur G.M., Nichols K.E., Plon S.E. et al. Pediatric cancer predisposition and surveillance: an overview, and a tribute to alfred G. Knudson Jr. Clin Cancer Res 2017;23(11):e1–5. DOI: 10.1158/1078-0432.CCR-17-0702Scott R.H., Stiller C.A., Walker L. et al. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet 2006;43(9):705–15. DOI: 10.1136/jmg.2006.041723Scott R.H., Douglas J., Baskcomb L. et al. Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor. Nat Genet 2008;40(11):1329–34. DOI: 10.1038/ng.243Maas S.M., Vansenne F., Kadouch D.J. et al. Phenotype, cancer risk, and surveillance in Beckwith–Wiedemann syndrome depending on molecular genetic subgroups. Am J Med Genet A 2016;170(9): 2248–60. DOI: 10.1002/ajmg.a.37801Scollon S., Anglin A.K., Thomas M. et al. A comprehensive review of pediatric tumors and associated cancer predisposition syndromes. J Genet Couns 2017;26(3):387–434. DOI: 10.1007/s10897-017-0077-8Hameed M., Mandelker D. Tumor syndromes predisposing to osteosarcoma. Adv Anat Pathol 2018;25(4):217–22. DOI: 10.1097/PAP.0000000000000190Treger T.D., Chowdhury T., Pritchard-Jones K., Behjati S. The genetic changes of Wilms tumour. Nat Rev Nephrol 2019;15(4):240–51. DOI: 10.1038/s41581-019-0112-0Mahamdallie S., Yost S., Poyastro-Pearson E. et al. Identification of new Wilms tumour predisposition genes: an exome sequencing study. Lancet Child Adolesc Health 2019;3(5):322–31. DOI: 10.1016/S2352-4642(19)30018-5Astuti D., Morris M.R., Cooper W.N. et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat Genet 2012;44(3):277–84. DOI: 10.1038/ng.1071Shuman C., Smith A.C., Steele L. et al. Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies. Am J Med Genet A 2006;140(14):1497–503. DOI: 10.1002/ajmg.a.31323Dommering C.J., Mol B.M., Moll A.C. et al. RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients. J Med Genet 2014;51(6):366–74. DOI: 10.1136/jmedgenet-2014-102264Dimaras H., Corson T.W., Cobrinik D. et al. Retinoblastoma. Nat Rev Dis Primers 2015;1:15021. DOI: 10.1038/nrdp.2015.21Lohmann D.R., Gallie B.L. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J Med Genet C Semin Med Genet 2004;129C(1):23–8. DOI: 10.1002/ajmg.c.30024Kulyova S.A., Imyanitov E.N. Wilm’s tumor: syndrome-based and molecular diagnostics. Onkopediatria 2017;4(4):283–9. (In Russ.). DOI: 10.15690/onco.v4i4.1814Кулева С.А., Имянитов Е.Н. Опухоль Вильмса: синдромальная и молекулярная диагностика. Онкопедиатрия 2017;4(4):283–9. DOI: 10.15690/onco.v4i4.1814Segers H., Kersseboom R., Alders M. et al. Frequency of WT1 and 11p15 constitutional aberrations and phenotypic correlation in childhood Wilms tumour patients. Eur J Cancer 2012;48(17):3249–56. DOI: 10.1016/j.ejca.2012.06.008Fischbach B.V., Trout K.L., Lewis J. et al. WAGR syndrome: a clinical review of 54 cases. Pediatrics 2005;116(4):984–8. DOI: 10.1542/peds.2004-0467Weksberg R., Nishikawa J., Caluseriu O. et al. Tumor development in the Beckwith–Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet 2001;10(26):2989–3000. DOI: 10.1093/hmg/10.26.2989Smith A.C., Squire J.A., Thorner P. et al. Association of alveolar rhabdomyosarcoma with the Beckwith–Wiedemann syndrome. Pediatr Dev Pathol 2001;4(6):550–8. DOI: 10.1007/s10024001-0110-6.Pappas J.G. The clinical course of an overgrowth syndrome, from diagnosis in infancy through adulthood: the case of Beckwith–Wiedemann syndrome. Curr Probl Pediatr Adolesc Health Care 2015;45(4):112–7. DOI: 10.1016/j.cppeds.2015.03.001Cooper W.N., Luharia A., Evans G.A. et al. Molecular subtypes and phenotypic expression of Beckwith–Wiedemann syndrome. Eur J Hum Genet 2005;13(9):1025–32. DOI: 10.1038/sj.ejhg.5201463Rahman N. Realizing the promise of cancer predisposition genes [published correction appears in Nature 2014;510(7503):176]. Nature 2014;505(7483):302–8. DOI: 10.1038/nature12981Nance M.A., Neglia J.P., Talwar D. et al. Neuroblastoma in a patient with Sotos’ syndrome. J Med Genet 1990;27(2):130–2. DOI: 10.1136/jmg.27.2.130Fagali C., Kok F., Nicola P. et al. MLPA analysis in 30 Sotos syndrome patients revealed one total NSD1 deletion and two partial deletions not previously reported. Eur J Med Genet 2009;52(5):333–6. DOI: 10.1016/j.ejmg.2009.07.001Cottereau E., Mortemousque I., Moizard M.P. et al. Phenotypic spectrum of Simpson–Golabi–Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature. Am J Med Genet C Semin Med Genet 2013;163C(2):92–105. DOI: 10.1002/ajmg.c.31360Ripperger T., Bielack S.S., Borkhardt A. 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.38142Gambale A., Russo R., Andolfo I. et al. Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition. Clin Genet 2019;96(4):359–65. DOI: 10.1111/cge.13600Dehainault C., Garancher A., Castéra L. et al. The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion. Hum Mol Genet 2014;23(19):5243–50. DOI: 10.1093/hmg/ddu245Taylor M., Dehainault C., Desjardins L. et al. Genotype-phenotype correlations in hereditary familial retinoblastoma. Hum Mutat 2007;28(3):284–93. DOI: 10.1002/humu.20443Imperatore V., Pinto A.M., Gelli E. et al. Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma. Eur J Hum Genet 2018;26(7):1026–37. DOI: 10.1038/s41431-017-0054-6Rushlow D.E., Mol B.M., Kennett J.Y. et al. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 2013;14(4):327–34. DOI: 10.1016/S1470-2045(13)70045-7Chen Z., Moran K., Richards-Yutz J. et al. Enhanced sensitivity for detection of low-level germline mosaic RB1 mutations in sporadic retinoblastoma cases using deep semiconductor sequencing. Hum Mutat 2014;35(3):384–91. DOI: 10.1002/humu.22488Amitrano S., Marozza A., Somma S. et al. Next generation sequencing in sporadic retinoblastoma patients reveals somatic mosaicism. Eur J Hum Genet 2015;23(11):1523–30. DOI: 10.1038/ejhg.2015.6Cygan K.J., Soemedi R., Rhine C.L. et al. Defective splicing of the RB1 transcript is the dominant cause of retinoblastomas. Hum Genet 2017;136(9):1303–12. DOI: 10.1007/s00439-017-1833-4Mendoza P.R., Grossniklaus H.E. The biology of retinoblastoma. Prog Mol Biol Transl Sci 2015;134:503–16. DOI: 10.1016/bs.pmbts.2015.06.012Correa H. Li-Fraumeni syndrome. J Pediatr Genet 2016;5(2):84–8. DOI: 10.1055/s-0036-1579759Villani A., Shore A., Wasserman J.D. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: 11-year follow-up of a prospective observational study. Lancet Oncol 2016;17(9):1295–305. DOI: 10.1016/S1470-2045(16)30249-2Frebourg T., Bajalica Lagercrantz S., Oliveira C. et al. Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet 2020;28(10):1379–86. DOI: 10.1038/s41431-020-0638-4Bougeard G., Renaux-Petel M., Flaman J.M. et al. Revisiting Li–Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 2015;33(21):2345–52. DOI: 10.1200/JCO.2014.59.5728Sherborne A.L., Lavergne V., Yu K. et al. Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors. Clin Cancer Res 2017;23(7):1852–61. DOI: 10.1158/1078-0432.CCR-16-0610Mirabello L., Yeager M., Mai P.L. et al. Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst 2015;107(7):djv101. DOI: 10.1093/jnci/djv101Birch J.M., Alston R.D., McNally R.J. et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 2001;20(34):4621–8. DOI: 10.1038/sj.onc.1204621Ognjanovic S., Olivier M., Bergemann T.L., Hainaut P. Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 2012;118(5):1387–96. DOI: 10.1002/cncr.26390De Kock L., Wu M.K., Foulkes W.D. Ten years of DICER1 mutations: provenance, distribution, and associated phenotypes. Hum Mutat 2019;40(11):1939–53. DOI: 10.1002/humu.23877De Kock L., Geoffrion D., Rivera B. et al. Multiple DICER1-related tumors in a child with a large interstitial 14q32 deletion. Genes Chromosomes Cancer 2018;57(5):223–30. DOI: 10.1002/gcc.22523McCluggage W.G., Apellaniz-Ruiz M., Chong A.L. et al. Embryonal rhabdomyosarcoma of the ovary and fallopian tube: rare neoplasms associated with germline and somatic DICER1 mutations. Am J Surg Pathol 2020;44(6):738–47. DOI: 10.1097/PAS.0000000000001442González I.A., Stewart D.R., Schultz K.A.P. et al. DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma. Mod Pathol 2022;35(1):4–22. DOI: 10.1038/s41379-021-00905-8Palculict T.B., Ruteshouser E.C., Fan Y. et al. Identification of germline DICER1 mutations and loss of heterozygosity in familial Wilms tumour. J Med Genet 2016;53(6):385–8. DOI: 10.1136/jmedgenet-2015-103311Doros L., Yang J., Dehner L. et al. DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome. Pediatr Blood Cancer 2012;59(3):558–60. DOI: 10.1002/pbc.24020Yin R., Kwoh C.K., Zheng J. Whole genome sequencing analysis. In: Encyclopedia of Bioinformatics and Computational Biology. Eds.: S. Ranganathan, M. Gribskov, K. Nakai, C. Schönbach. Academic Press, 2019. Pp. 176–183.Tam V., Patel N., Turcotte M. et al. Benefits and limitations of genome-wide association studies. Nat Rev Genet 2019;20(8):467–84. DOI: 10.1038/s41576-019-0127-1Parsons D.W., Roy A., Yang Y. et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol 2016;2(5):616–24. DOI: 10.1001/jamaoncol.2015.5699