D Pasquali1, A Torella2,3, G Accardo4, D Esposito5, F Del Vecchio Blanco2, D Salvatore6, P Sabatino7, F Pacini8, F Barbato8, M G Castagna8, S Cantara8, V Nigro2,3. 1. Department of Medical and Surgical Advanced Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. daniela.pasquali@unicampania.it. 2. Genetica Medica, Dipartimento di Medicina di Precisione, University of Campania"Luigi Vanvitelli", Naples, Italy. 3. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy. 4. Department of Medical and Surgical Advanced Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. 5. Department of Endocrinology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden. 6. Department of Public Health, University of Naples "Federico II", Naples, Italy. 7. Azienda Sanitaria Locale Salerno, Naples, Italy. 8. Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
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.
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.
Entities:
Keywords:
BROX; EGFR; FNMTC; HABP2; NGS; Thyroid; Thyroid cancer
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