Abstract
The sonic hedgehog (SHH) signaling pathway has been shown to play important roles in embryogenesis, cell proliferation as well as in cell differentiation. It is aberrantly activated in various common cancers in adults, but also in pediatric neoplasms, such as rhabdomyosarcoma (RMS) and atypical teratoid/rhabdoid tumors (AT/RTs). Dysregulation and germline mutation in PATCHED1 (PTCH1), a receptor for SHH, is responsible for the Gorlin Syndrome, a familial cancer predisposing syndrome including RMS. Here, we report a newborn diagnosed with congenital embryonal RMS. Whole-exome sequencing (WES) identified the presence of two heterozygous germline mutations in two target genes of the SHH signaling pathway. The PTCH1 mutation p.(Gly38Glu) is inherited from the mother, whereas the PTCH2 p.(His622Tyr) mutation is transmitted from the father. Quantitative RT-PCR expression analysis of GLI and SMO, key players of the SHH pathway, showed significantly increase in the tumor tissue of the patient and also enrichment in the germline sample in comparison to the parents indicating activation of the SHH pathway in the patient. These findings demonstrate that SHH pathway activity seems to play a role in eRMS as evidenced by high expression levels of GLI1 RNA transcripts. We speculate that PTCH2 modulates tumorigenesis linked to the PTCH1 mutation and is likely associated with the congenital onset of the RMS observed in our patient.
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Acknowledgements
This work was supported by the Elterninitiative Kinderkrebsklinik e.V. Duesseldorf and by the BMBF (to SF). We wish to thank Mrs. S. Furlan and Mrs. K. Alemazkour for technical assistance, Prof. Dr. I. Leuschner for pathologic analyses, Prof. Dr. M. Dugas and C. Walter for WES data analyses and establishment of the bioinformatics pipeline as well as Dr. J.I. Hoell for critical reading of the manuscript.
Author contributions
JT and MK drafted the manuscript. JT performed the experiments with help of NQ and JB. TB obtained informed consent, asked for the family history, and cared for the child. JS performed the radiological diagnostic. SG was responsible for the internal SQL database. JF contributed to pathology analysis. SF contributed to the design of the experiments and data analysis. CV performed pathologic analyses. AB and MK designed and supervised the project. AB critically revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted.
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The study was approved by the ethics committee of the Heinrich-Heine-University Duesseldorf, Germany.
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Written informed consent was obtained from both the parents.
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Arndt Borkhardt and Michaela Kuhlen contributed equally to this work.
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Taeubner, J., Brozou, T., Qin, N. et al. Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations. Eur J Hum Genet 26, 137–142 (2018). https://doi.org/10.1038/s41431-017-0048-4
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DOI: https://doi.org/10.1038/s41431-017-0048-4
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