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

Sculco, Marika; Vecchia, Marta La; 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

doi:10.3390/diagnostics12071710

Cited by 7 publications

(10 citation statements)

References 53 publications

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“…Many studies have focused on genetic mutations [ 5 , 30 ] or epigenetic mechanisms [ 31 ] of mesothelioma and found common patterns with other cancers. Several findings have suggested a potential role for BAP1 in the carcinogenesis of numerous malignancies [ 32 , 33 , 34 , 35 ]. BAP1 is an oncosuppressor protein that acts as a deubiquitinase and is involved in gene expression and chromatin regulation [ 34 , 35 , 36 ]; it is commonly inactivated in mesotheliomas [ 7 , 37 , 38 , 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several findings have suggested a potential role for BAP1 in the carcinogenesis of numerous malignancies [ 32 , 33 , 34 , 35 ]. BAP1 is an oncosuppressor protein that acts as a deubiquitinase and is involved in gene expression and chromatin regulation [ 34 , 35 , 36 ]; it is commonly inactivated in mesotheliomas [ 7 , 37 , 38 , 39 , 40 ]. Germline BAP1 mutations underpin the BAP1 tumor predisposition syndrome (BAP1-TPDS).…”

Section: Discussionmentioning

confidence: 99%

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Second Primary Cancers in a Population-Based Mesothelioma Registry

Mensi

Stella

Dallari

et al. 2023

Cancers

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Background: The presence of a second primary cancer (SPC) in patients with pleural mesothelioma (PM) may impact overall survival and suggest a common mechanism of carcinogenesis or an underlying germline genetic alteration. Methods: We evaluated the occurrence of SPCs within PM cases collected from 2000 to 2018 by the Lombardy Mesothelioma Registry and their prognostic implications. Kaplan–Meier analysis was performed to estimate median survival times, together with univariate and multivariate Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) of death. Results: The median overall survival (OS) of the entire study population (N = 6646) was 10.9 months (95% CI: 10.4–11.2); patient age and histotype were the strongest prognostic factors. No substantial survival difference was observed by the presence of an SPC (10.5 months in 1000 patients with an SPC vs. 10.9 months in 5646 patients in the non-SPC group, HR 1.03, p = 0.40). Shorter OS in the SPC group was only observed in 150 patients with the non-epithelioid subtype (median OS of 5.4 vs. 7.1 months, HR 1.21, p = 0.03). Conclusions: The diagnosis of an SPC did not influence the outcome of PM patients in the overall study population but was associated with shorter OS in non-epithelioid cases. Further studies are needed to clarify the role of SPCs as markers of genetic susceptibility in mesothelioma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Second Primary Cancers in a Population-Based Mesothelioma Registry

Mensi

Stella

Dallari

et al. 2023

Cancers

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“…Nevertheless, germline variants associated with KURIS have been reported as somatic tumor variants in a handful of patients. 3,17 T A B L E 1 Reported germline variants of BAP1 associated with tumor predisposition syndrome 1 (TPDS1) or Kury-Isidor syndrome (KURIS). As mentioned earlier, these variants elevate the risk of multiple cancer types, characterized by aggressiveness, rapid growth, and earlier onset compared to sporadic cases.…”

Section: Bap1 Functionmentioning

confidence: 99%

“…This may be due to underreporting of family histories that are not cancer related. Nevertheless, germline variants associated with KURIS have been reported as somatic tumor variants in a handful of patients 3,17 …”

Section: Bap1 Functionmentioning

confidence: 99%

BRCA1‐associated protein 1: Tumor predisposition syndrome and Kury‐Isidor syndrome, from genotype–phenotype correlation to clinical management

West,

Chiappetta,

Mattingly

et al. 2024

Clinical Genetics

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The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1‐TPDS1) and a neurodevelopmental disorder known as Kury‐Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype–phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols.

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“…In general, carriers of the germline BAP1 pathogenic variant (PV) develop tumors at a younger age as compared to patients with the same sporadic tumors [6] (Table 3). A recent Italian study by Sculco et al [33] describing a ten years in the molecular diagnosis of BAP1-TPDS sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated PVs by assessing BAP1 somatic loss in matching tumor specimens. Overall, the authors found seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant.…”

Section: Role Of Bap1 Protein Loss In the Diagnosis Of Bap1 Syndromementioning

confidence: 99%

BAP1 Loss, Nuclear Grading, and Nonepithelioid Features in the Diagnosis of Mesothelioma in Italy: Nevermore without the Pathology Report

Rossi,

Righi,

Barbisan

et al. 2024

JPM

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The pathologic diagnosis of pleural mesothelioma is generally based on international guidelines, but no compulsory points based on different drugs approvals in different European countries are required to be reported. According to the last (2021) edition of the World Health Organization classification of pleural tumors, the nuclear grade of epithelioid-type mesothelioma should be always inserted in the pathologic report, while the presence of BRCA-associated protein-1 (BAP1) (clone C4) loss and a statement on the presence of the sarcomatoid/nonepithelioid component are fundamental for both a screening of patients with suspected BAP1 tumor predisposition syndrome and the eligibility to perform first-line immunotherapy at least in some countries. Several Italian experts on pleural mesothelioma who are deeply involved in national scientific societies or dedicated working groups supported by patient associations agreed that the pathology report of mesothelioma of the pleura should always include the nuclear grade in the epithelioid histology, which is an overt statement on the presence of sarcomatoid components (at least 1%, in agreement with the last classification of pleural mesothelioma) and the presence of BAP1 loss (BAP1-deficient mesothelioma) or not (BAP1-retained mesothelioma) in order to screen patients possibly harboring BAP1 tumor predisposition syndrome. This review aims to summarize the most recent data on these three important elements to provide evidence regarding the possible precision needs for mesothelioma.

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

Cited by 7 publications

References 53 publications

Second Primary Cancers in a Population-Based Mesothelioma Registry

Second Primary Cancers in a Population-Based Mesothelioma Registry

BRCA1‐associated protein 1: Tumor predisposition syndrome and Kury‐Isidor syndrome, from genotype–phenotype correlation to clinical management

BAP1 Loss, Nuclear Grading, and Nonepithelioid Features in the Diagnosis of Mesothelioma in Italy: Nevermore without the Pathology Report

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