Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience

Sculco, Marika;La Vecchia, Marta;Witel, Gianluca;Napoli, Francesca;Grosso, Federica;Rena, Ottavio;Giachino, Daniela;Bironzo, Paolo;Righi, Luisella;Tampieri, Cristian;Scagliotti, Giorgio Vittorio;Ferrante, Daniela;Migliore, Enrica;Matullo, Giuseppe;
2022-01-01

Abstract

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.
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BAP1-TPDS; cancer genome; diagnostics; germline variants; immunohistochemistry; melanoma; mesothelioma
Sculco, Marika; La Vecchia, Marta; Aspesi, Anna; Clavenna, Michela Giulia; Salvo, Michela; Borgonovi, Giulia; Pittaro, Alessandra; Witel, Gianluca; Napoli, Francesca; Listì, Angela; Grosso, Federica; Libener, Roberta; Maconi, Antonio; Rena, Ottavio; Boldorini, Renzo; Giachino, Daniela; Bironzo, Paolo; Maffè, Antonella; Alì, Greta; Elefanti, Lisa; Menin, Chiara; Righi, Luisella; Tampieri, Cristian; Scagliotti, Giorgio Vittorio; Dianzani, Caterina; Ferrante, Daniela; Migliore, Enrica; Magnani, Corrado; Mirabelli, Dario; Matullo, Giuseppe; Dianzani, Irma
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1878603
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