Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations

Carbone, Michele; Pass, Harvey I.; Ak, Güntülü; Alexander, H. Richard; Baas, Paul; Baumann, Francine; Blakely, Andrew M.; Bueno, Raphael; Bzura, Aleksandra; Cardillo, Giuseppe; Churpek, Jane E.; Dianzani, Irma; Rienzo, Assunta De; Emi, Mitsuru; Emri, Salïh; Felley-Bosco, Emanuela; Fennell, Dean A.; Flores, Raja M.; Grosso, Federica; Hayward, Nicholas K.; Hesdorffer, Mary; Hoang, Chuong D.; Johansson, Peter; Kindler, Hedy L.; Kittaneh, Muaiad; Krausz, Thomas; Mansfield, Aaron S.; Metintaş, Muzaffer; Minaai, Michael; Mutti, Luciano; Nielsen, Maartje; O’Byrne, Kenneth J.; Opitz, Isabelle; Pastorino, Sandra; Pentimalli, Francesca; Perrot, Marc de; Pritchard, Antonia L.; Ripley, R. Taylor; Robinson, B. W.; Rusch, Valerie W.; Taioli, Emanuela; Takinishi, Yasutaka; Tanji, Mika; Tsao, Anne S.; Tuncer, Aziz; Walpole, Sebastian; Wolf, Andrea; Yang, Haining; Yoshikawa, Yasuhiro; Zolodnick, Alicia; Schrump, David S.; Hassan, Raffit

doi:10.1016/j.jtho.2022.03.014

Cited by 51 publications

(83 citation statements)

References 103 publications

(169 reference statements)

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“…Interestingly, patient MPM_HO1901 (II-3) is still alive, 27 months after the diagnosis, and, since she is positive for a mutation in BAP1 , has been recruited in a trial aiming to test the combination of immunotherapy and PARP inhibitors as second-line treatment (NCT04940637) [ 46 ]. These results agree with previous studies showing prolonged survival of PlM TPDS patients compared to that of sporadic patients [ 8 , 9 , 12 , 14 , 15 , 16 , 17 , 18 ].…”

Section: Discussionsupporting

confidence: 93%

“…BAP1 -TPDS is inherited in an autosomal dominant fashion [ 2 , 5 , 8 , 9 , 10 , 11 ] with a penetrance close to 100% in older age individuals [ 7 , 12 ]. In general, carriers of germline BAP1 PVs develop tumors at a younger age than that of sporadic patients [ 4 , 7 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have shown that many—but not all—mesothelioma patients with germline BAP1 -TPDS are characterized by prolonged survival compared to wild-type (wt) BAP1 patients [ 8 , 9 , 12 , 14 , 15 , 16 , 17 , 18 ]. In contrast, BAP1 PV carriers affected by melanoma—both cutaneous and uveal—exhibit increased risk of metastasis, suggesting a shorter survival rate [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

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“…The identification of genetic mutations in family members affected by MM, and as in our case, by other pathologies included in BPA1-TPDS, must alert doctors to implement genetic counselling, screening measures, and therapeutic measures for oncological pathologies ( 47 ). The importance of detecting families affected by this type of mutation must be evaluated with a view to primary prevention, since it is necessary to protect these families from exposure to various carcinogens, both environmental and occupational, to prevent the development of malignant diseases.…”

Section: Discussionmentioning

confidence: 91%

“…Many studies have evaluated blood-related cases of mesothelioma involving several members of the same family ( 6 , 7 ). Walpole ( 13 ) reported 181 different families worldwide carrying BAP1 mutations; however, this syndrome remains under-recognized and under-reported ( 20 , 47 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: Mesothelioma and BAP1 tumor predisposition syndrome: Implications for public health

et al. 2022

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BRCA-1 associated protein 1 (BAP1) tumour predisposition syndrome (TPDS) is a hereditary condition characterised by germline mutation of the tumour suppressor BAP1. This disorder is associated with the development of various benign and malignant tumours, mainly involving the skin, eyes, kidneys, and mesothelium. In this article, we report the case of a man recruited through the Apulia (Southern Italy) Mesothelioma Regional Operational Centre of the National Register of Mesotheliomas, who suffered from uveal melanoma, renal cancer, and mesothelioma, and a familial cluster of BAP1 germline mutations demonstrated by molecular analyses. The family members of the proband developed multiple malignancies. As tumours arising in this context have specific peculiarities in terms of clinical behaviour, identification of this condition through appropriate genetic counselling should be considered for adequate primary, secondary, and tertiary prevention measures for offspring.

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Multiple Onychopapillomas and BAP1 Tumor Predisposition Syndrome

Lebensohn,

Ghafoor,

Bloomquist

et al. 2024

JAMA Dermatol

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ImportanceBRCA1-associated protein (BAP1) tumor predisposition syndrome (TPDS) is a cancer genodermatosis associated with high risk of uveal and cutaneous melanoma, basal cell carcinoma, and multiple internal malignant neoplasms, including mesothelioma and renal cell carcinoma. Early detection of the syndrome is important for cancer surveillance and genetic counseling of family members who are at risk.ObjectiveTo determine the prevalence of nail abnormalities in individuals with pathogenic germline variants in BAP1.Design, Setting, and ParticipantsIn this prospective cohort study, individuals who were known carriers of pathogenic BAP1 germline variants were consecutively enrolled between October 10, 2023, and March 15, 2024. Dermatologic evaluation for nail abnormalities was performed, including a history of nail abnormalities and associated symptoms, physical examination, medical photography, and nail biopsy for histopathology. This was a single-center study conducted at the National Institutes of Health Clinical Center.Main Outcomes and MeasuresPrimary outcomes were the prevalence and spectrum of nail changes and histopathologic characterization.ResultsAmong 47 participants (30 female [63.8%]; mean [SD] age, 46.4 [15.1] years) ranging in age from 13 to 72 years from 35 families, nail abnormalities were detected in 41 patients (87.2%) and included leukonychia, splinter hemorrhage, onychoschizia, and distal nail hyperkeratosis. Clinical findings consistent with onychopapilloma were detected in 39 patients (83.0%), including 35 of 40 individuals aged 30 years or older (87.5%). Nail bed biopsy was performed in 5 patients and was consistent with onychopapilloma. Polydactylous involvement with onychopapillomas was detected in nearly all patients who had nail involvement (38 of 39 patients [97.4%]).Conclusions and RelevanceThis study found that BAP1 TPDS was associated with a high rate of nail abnormalities consistent with onychopapillomas in adult carriers of the disease. Findings suggest that this novel cutaneous sign may facilitate detection of the syndrome in family members who are at risk and patients with cancers associated with BAP1 given that multiple onychopapillomas are uncommon in the general population and may be a distinct clue to the presence of a pathogenic germline variant in the BAP1 gene.

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Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations

Cited by 51 publications

References 103 publications

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

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

Case report: Mesothelioma and BAP1 tumor predisposition syndrome: Implications for public health

Multiple Onychopapillomas and BAP1 Tumor Predisposition Syndrome

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