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Extraskeletal chondroma of the toe in a child with DICER1 tumor predisposition syndrome: support for a dominant negative mechanism

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Abstract

DICER1 tumor predisposition syndrome is a pleiotropic disorder that gives rise to various mainly pediatric-onset lesions. We report an extraskeletal chondroma (EC) of the great toe occurring in a child who, unusually, carries a germline “hotspot” missense DICER1 variant rather than the more usual loss-of-function (LOF) variant. No heterozygous LOF allele was identified in the EC. We demonstrate this variant impairs 5p cleavage of precursor-miRNA (pre-miRNA) and competes with wild-type (WT) DICER1 protein for pre-miRNA processing. These results suggest a mechanism through which a germline RNase IIIb variant could impair pre-miRNA processing without complete LOF of the WT DICER1 allele.

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Fig. 1
Fig. 2

Data Availability

Full tumor sequencing data are available on reasonable request.

Abbreviations

DTPS:

DICER1 tumor predisposition syndrome

EC:

Extraskeletal chondroma

FFPE:

Formalin-fixed paraffin-embedded

GPV:

Germline pathogenic variant

LOF:

Loss of function

LOH:

Loss of heterozygosity

NGS:

Next-generation sequencing

pre-miRNA:

Precursor-mirna

RNase:

Ribonuclease

WT:

Wild-type

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Acknowledgements

We thank Nancy Hamel for helpful comments.

Funding

Funded by a Canadian Institutes of Health Grant (CIHR) to WDF (FDN-148390). M.R.F. is funded by the CIHR grant [PJT-156356]; Natural Science and Engineering Research Council of Canada (NSERC); Discovery grant [RGPIN-2015–03712]; Fonds de recherche du Quebec-Santé (FRQS) Chercheur-Boursier Senior award. D.P. is supported by the CIHR (CGS-M).

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Authors and Affiliations

  1. Department of Human Genetics, Medicine, McGill University, Montreal, QC, Canada

    Dylan Pelletier, Nelly Sabbaghian, Anne-Laure Chong & William D. Foulkes

  2. Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada

    Dylan Pelletier, Nelly Sabbaghian, Anne-Laure Chong, Marc R. Fabian & William D. Foulkes

  3. Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Dylan Pelletier

  4. Minneapolis, USA

    John R. Priest

  5. Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Yomna Elsheikh Ahmed

  6. Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen, Bahrain

    Yomna Elsheikh Ahmed & Gabriel P. Fox

  7. King Hamad University Hospital, Al Sayh, Bahrain

    Yomna Elsheikh Ahmed & Gabriel P. Fox

  8. Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada

    Marc R. Fabian & William D. Foulkes

  9. Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, QC, Canada

    William D. Foulkes

Authors
  1. Dylan Pelletier
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  2. Nelly Sabbaghian
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  3. Anne-Laure Chong
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  4. John R. Priest
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  5. Yomna Elsheikh Ahmed
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  6. Gabriel P. Fox
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  7. Marc R. Fabian
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  8. William D. Foulkes
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Contributions

Laboratory work: DP, ALC, NS; writing: DP, JRP, WDF; clinical support and tissue acquisition: YEA, GPF; overseeing of laboratory work: MRF, WDF; final approval of manuscript: all authors.

Corresponding author

Correspondence to William D. Foulkes.

Ethics declarations

This study was performed in accordance with the Declaration of Helsinki and approved by the Canadian institute of health research (MP-37–2019-4865) and ethics committee of the Research Institute of the McGill University Health Center. The patient mother signed the consent form on behalf of the patient.

Conflict of interest

The authors declare no competing interests.

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Pelletier, D., Sabbaghian, N., Chong, AL. et al. Extraskeletal chondroma of the toe in a child with DICER1 tumor predisposition syndrome: support for a dominant negative mechanism. Virchows Arch (2024). https://doi.org/10.1007/s00428-024-03759-y

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  • DOI: https://doi.org/10.1007/s00428-024-03759-y

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