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Published on: September 13, 2019
Cancer predisposition genes in Japanese children with rhabdomyosarcoma
Hiroko Fukushima1,2, Ryoko Suzuki3,4, Yuni Yamaki3
1Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan. fkhiroko@md.tsukuba.ac.jp.
Insights
Germline variants in genes like DICER1, TP53, BUB1B, LIG4, and MEN1 were identified in pediatric rhabdomyosarcoma (RMS) patients. This study provides crucial insights into the genetic landscape of RMS in Asian children.
Area of Science:
- Pediatric Oncology
- Cancer Genetics
- Molecular Biology
Background:
- Rhabdomyosarcoma (RMS) is a common pediatric soft tissue sarcoma.
- Germline mutations in cancer-predisposition genes are found in about 10% of pediatric cancers.
- The genetic basis of RMS, particularly in Asian populations, remains largely unknown.
Purpose of the Study:
- To investigate the germline genetic background of rhabdomyosarcoma in Japanese children.
- To identify pathogenic variants in cancer-predisposition genes associated with pediatric RMS.
- To correlate genetic findings with clinical outcomes and family history.
Main Methods:
- Targeted re-sequencing of cancer-associated genes.
- DNA analysis from peripheral blood samples of pediatric RMS patients.
- Clinical data collection including outcomes and family history.
Main Results:
- Six pathogenic variants were identified in five out of twenty pediatric RMS patients.
- Variants included DICER1 (nonsense), TP53 (exon deletion), and BUB1B, LIG4, MEN1 (missense).
- LIG4 missense variants, crucial for DNA repair, were found in two unrelated patients, linked to drug-induced cardiomyopathy.
Conclusions:
- This study presents the first germline genetic analysis of Japanese children with RMS, showing variant frequencies comparable to Western cohorts.
- Identified variants in DICER1, TP53, BUB1B, LIG4, and MEN1 contribute to understanding RMS pathogenesis.
- Unbiased exon sequencing may aid in clarifying RMS pathogenesis and predicting patient clinical course.
Abstract:
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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