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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.


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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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