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Cancer predisposition genes in Japanese children with rhabdomyosarcoma


Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children. Germline mutations in cancer-predisposition genes have been detected in approximately 10% of pediatric cancers. However, the genetic background of RMS is still unclear, especially in Asian children. DNA was extracted from the peripheral blood of children with RMS and cancer-associated genes analyzed using targeted re-sequencing. Twenty patients participated in this study. There were three deaths due to RMS. One patient developed a second neoplasm. Nine patients had long-term co-morbidities. Six pathogenic variants were found in five patients: one nonsense variant of DICER1, one exon deletion of TP53, and three missense variants of BUB1B, LIG4, and MEN1. Two of the five patients had a family history of cancer. Two patients with missense variants of LIG4 had long-term co-morbidities of drug-induced cardiomyopathy. The missense variants of LIG4, essential for DNA double-strand break repair, were detected in two unrelated patients. While this is the first report of the germline genetic analysis of Japanese children with RMS with detailed clinical information, the frequency of the variant was almost equivalent to that of previous reports from western countries. Unbiased exon sequencing may be useful to clarify the pathogenesis of RMS in children and in predicting the clinical course of these patients.

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Fig. 1: Family trees of the detected patients.
Fig. 2: Detected variant location in DICER1.
Fig. 3: Variant location and structural analysis of the detected variant in BUB1B.
Fig. 4: Variant location and structural analysis of the detected variant in LIG4.
Fig. 5: Variant location and structural analysis of the detected variant in MEN1.

Data availability

Data will be disclosed when appropriate after contacting the corresponding author.


  1. Nakata K, Ito Y, Magadi W, Bonaventure A, Stiller CA, Katanoda K, et al. Childhood cancer incidence and survival in Japan and England: a population-based study (1993-2010). Cancer Sci. 2018;109:422–34.

    Article  CAS  Google Scholar 

  2. Parsons DW, Roy A, Yang Y, Wang T, Scollon S, Bergstrom K, et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol. 2016;2:616–24.

    Article  Google Scholar 

  3. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373:2336–46.

    Article  CAS  Google Scholar 

  4. Gröbner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, et al. The landscape of genomic alterations across childhood cancers. Nature. 2018;555:321–27.

    Article  Google Scholar 

  5. 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;36:591–99.

    Article  CAS  Google Scholar 

  6. Le AN, Harton J, Desai H, Powers J, Zelley K, Bradbury AR, et al. Frequency of radiation-induced malignancies post-adjuvant radiotherapy for breast cancer in patients with Li-Fraumeni syndrome. Breast cancer Res Treat. 2020;181:181–88.

    Article  CAS  Google Scholar 

  7. Frebourg T, Bajalica Lagercrantz S, Oliveira C, Magenheim R, Evans DG. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet. 2020;28:1379–86.

    Article  CAS  Google Scholar 

  8. Li H, Sisoudiya SD, Martin-Giacalone BA, Khayat MM, Dugan-Perez S, Marquez-Do DA, et al. Germline cancer-predisposition variants in pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group. J Natl Cancer Inst. 2021;113:875–83.

  9. Kim J, Light N, Subasri V, Young EL, Wegman-Ostrosky T, Barkauskas DA, et al. Pathogenic germline variants in cancer susceptibility genes in children and young adults with rhabdomyosarcoma. JCO Precis Oncol. 2021;5:75–87.

  10. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.

    Article  Google Scholar 

  11. Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40:W452–7.

    Article  CAS  Google Scholar 

  12. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    Article  CAS  Google Scholar 

  13. Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 2011;39:e118.

    Article  CAS  Google Scholar 

  14. Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.

    Article  CAS  Google Scholar 

  15. Fukushima H, Fukushima T, Sakai A, Suzuki R, Nakajima-Yamaguchi R, Kobayashi C, et al. Polymorphisms of MTHFR associated with higher relapse/death ratio and delayed weekly MTX administration in pediatric lymphoid malignancies. Leuk Res Treat. 2013;2013:238528.

    Google Scholar 

  16. Pugh TJ, Yu W, Yang J, Field AL, Ambrogio L, Carter SL, et al. Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences. Oncogene. 2014;33:5295–302.

    Article  CAS  Google Scholar 

  17. Hosoi H, Teramukai S, Matsumoto Y, Tsuchiya K, Iehara T, Hara J, et al. A review of 331 rhabdomyosarcoma cases in patients treated between 1991 and 2002 in Japan. Int J Clin Oncol. 2007;12:137–45.

    Article  Google Scholar 

  18. Schultz KAP, Williams GM, Kamihara J, Stewart DR, Harris AK, Bauer AJ, et al. DICER1 and associated conditions: identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res. 2018;24:2251–61.

    Article  CAS  Google Scholar 

  19. Doros L, Yang J, Dehner L, Rossi CT, Skiver K, Jarzembowski JA, et al. DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome. Pediatr Blood Cancer. 2012;59:558–60.

    Article  Google Scholar 

  20. Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D, et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet. 2004;36:1159–61.

    Article  CAS  Google Scholar 

  21. Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33:2345–52.

    Article  CAS  Google Scholar 

  22. Diller L, Sexsmith E, Gottlieb A, Li FP, Malkin D. Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Investig. 1995;95:1606–11.

    Article  CAS  Google Scholar 

  23. Hettmer S, Archer NM, Somers GR, Novokmet A, Wagers AJ, Diller L, et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer. 2014;120:1068–75.

    Article  CAS  Google Scholar 

  24. Villani A, Shore A, Wasserman JD, Stephens D, Kim RH, Druker H, 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;17:1295–305.

    Article  CAS  Google Scholar 

  25. Rio Frio T, Lavoie J, Hamel N, Geyer FC, Kushner YB, Novak DJ, et al. Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia. N Engl J Med. 2010;363:2628–37.

    Article  Google Scholar 

  26. O’Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001;8:1175–85.

    Article  Google Scholar 

  27. Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature. 2007;449:478–82.

    Article  CAS  Google Scholar 

  28. Balinska K, Wilk D, Filipek B, Mik M, Zelga P, Skubel P, et al. Association of XRCC6 C1310G and LIG4 T9I polymorphisms of NHEJ DNA repair pathway with risk of colorectal cancer in the Polish population. Pol Prz Chirurgiczny. 2019;91:15–20.

    Article  Google Scholar 

  29. Gao Y, Katyal S, Lee Y, Zhao J, Rehg JE, Russell HR, et al. DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair. Nature. 2011;471:240–4.

    Article  CAS  Google Scholar 

  30. Svoboda LK, Teh SSK, Sud S, Kerk S, Zebolsky A, Treichel S, et al. Menin regulates the serine biosynthetic pathway in Ewing sarcoma. J Pathol. 2018;245:324–36.

    Article  CAS  Google Scholar 

  31. Radman M, Milicevic T. A novel mutation of the MEN1 gene in a patient with multiple endocrine neoplasia type 1 and recurrent fibromyxoid sarcoma – a case report. BMC Med Genet. 2020;21:190.

    Article  CAS  Google Scholar 

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This work was partially supported by Grant-in-Aid for Young Scientists (B) from Japan Society for the Promotion of Science (17K16239). We would like to thank all participated patients/families and physicians who took care of children and Editage ( for English language editing.

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Authors and Affiliations



Study conception and design: HF and EN. Manuscript preparation: HF. Data acquisition: HF, RS, YY, SH, and MI. Critical revision for important intellectual content: RS, YY, SH, and MI. Genetic analysis: HF and WM. Critical and important advice particularly on genetic analysis: EN. Critical and important advice on the whole research conduction: HT.

Corresponding author

Correspondence to Hiroko Fukushima.

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The authors declare no competing interests.

Ethics approval and consent to participate

This work was approved by the institutional ethical review board of the University of Tsukuba Hospital (H27-167). This research was conducted in accordance with the Japan Ministry of Health, Labour and Welfare’s Guidance on Ethical Guidelines for Medical Research Involving Human Subjects and Ethical Guidelines for Human Genome Research, and the Declaration of Helsinki. Informed consent to participate in this study was obtained from all patients/parents.

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Fukushima, H., Suzuki, R., Yamaki, Y. et al. Cancer predisposition genes in Japanese children with rhabdomyosarcoma. J Hum Genet 67, 35–41 (2022).

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