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BROX haploinsufficiency in familial nonmedullary thyroid cancer

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Abstract

Background

The familial nonmedullary thyroid cancer (FNMTC) is suspected to be a Mendelian condition in up to 3–8% of thyroid cancers. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. The inheritance of FNMTC appears to be autosomal dominant with incomplete penetrance and variable expressivity. The finding of the causative gene of FNMTC and the identification of patients at risk that need genetic testing were our aim.

Methods

We analyzed by whole-exome sequencing patients and non-affected relatives of five families with at least two family members affected by papillary thyroid cancer, selecting for new or extremely rare variants with predicted pathogenic value.

Results

A family showed, in all three affected members, a new loss-of-function variant (frameshift deletion) in BROX gene at 1q41 that was absent from all internal and external databases. In a second family with three affected relatives, we found an additional new BROX variant. The smaller families presented no variants in BROX or in the other causative genes studied.

Conclusions

BROX could be a new causative gene for FNMTC. Variants in BROX may result in the haploinsufficiency of a key gene involved in the morphogenesis of MVBs, in the endosomal sorting of cargo proteins, and in EGFR. Functional studies are needed to support this result. The thorough genomic analysis by NGS in all families with three or more affected members should become a routine approach to obtain a comprehensive genetic view and find confirmative second cases.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the study participants, their families, and all the investigators and study staff members. VN Supported by grants from Telethon 2015 “Medicina Traslazionale in Oncologia: Dalla Ricerca alla Terapia PON01_02418”, Telethon 2016–2018 “Telethon Undiagnosed Disease Program”, 2018-22 EU Research Funding H2020-HEALTH-SC1-2017-RTD: “SOLVE RD”.

Funding

VN Supported by grants from Telethon 2015 “Medicina Traslazionale in Oncologia: Dalla Ricerca alla Terapia PON01_02418”, Telethon 2016–2018 “Telethon Undiagnosed Disease Program”, 2018-22 EU Research Funding H2020-HEALTH-SC1-2017-RTD: “SOLVE RD”.

Author information

Authors and Affiliations

  1. Department of Medical and Surgical Advanced Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy

    D. Pasquali & G. Accardo

  2. Genetica Medica, Dipartimento di Medicina di Precisione, University of Campania”Luigi Vanvitelli”, Naples, Italy

    A. Torella, F. Del Vecchio Blanco & V. Nigro

  3. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy

    A. Torella & V. Nigro

  4. Department of Public Health, University of Naples “Federico II”, Naples, Italy

    D. Salvatore

  5. Azienda Sanitaria Locale Salerno, Naples, Italy

    P. Sabatino

  6. Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy

    F. Pacini, F. Barbato, M. G. Castagna & S. Cantara

  7. Department of Endocrinology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden

    D. Esposito

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  1. D. Pasquali
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Corresponding author

Correspondence to D. Pasquali.

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Conflict of interest

The authors have nothing to disclose.

Ethics approval

The study was approved by the local ethical committee of the Università della Campania “Luigi Vanvitelli” protocol n°54 del 2/5/2019 on Horizon 2020 Solve the Unsolved project.

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The informed consent was obtained from the patients included in the study.

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Pasquali, D., Torella, A., Accardo, G. et al. BROX haploinsufficiency in familial nonmedullary thyroid cancer. J Endocrinol Invest 44, 165–171 (2021). https://doi.org/10.1007/s40618-020-01286-6

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  • DOI: https://doi.org/10.1007/s40618-020-01286-6

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