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

Our plain-English summary of Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience, by M. Sculco, M. La Vecchia, A. Aspesi, et al (Diagnostics, 2022).

The study

• Authors: M. Sculco, M. La Vecchia, A. Aspesi, M.G. Clavenna, M. Salvo, G. Borgonovi, A. Pittaro, G. Witel, F. Napoli, A. Listì, F. Grosso, R. Libener, A. Maconi, O. Rena, R. Boldorini, D. Giachino, P. Bironzo, A. Maffè, G. Alì, L. Elefanti, C. Menin, L. Righi, C. Tampieri, G.V. Scagliotti, C. Dianzani, D. Ferrante, E. Migliore, C. Magnani, D. Mirabelli, G. Matullo, I. Dianzani
• Journal: Diagnostics
• Published: 2022;12(7)
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This Italian study reported ten years of genetic testing for BAP1 tumor predisposition syndrome, an inherited condition that predisposes people to mesothelioma, melanoma and other tumors. The authors tested blood DNA from 101 suspected patients, chosen for a family history of cancer plus a tumor from the syndrome's range in the patient or a relative. They also examined carriers' tumor tissue. Seven of the 101 patients (6.9%; 95% confidence interval 2.8% to 13.8%) carried a disease-causing (pathogenic) BAP1 variant. Six different variants were found, one never described before. Nine relatives were also tested. Of four relatives who were healthy when found to carry a variant, three were later diagnosed with tumors of the syndrome. Some tumors in carriers still had a normal copy of BAP1. Of seven carriers with mesothelioma, the authors classed five as long-term survivors. The article did not report the patients' asbestos exposure. The authors concluded that carriers, including healthy relatives with a BAP1 variant, need appropriate surveillance. They also recommended confirming loss of both BAP1 copies in the tumor before patients join precision-medicine trials.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Report of a ten-year clinical genetic diagnostic program (germline testing of suspected cases, with tumor tissue analyses and family cascade testing)
• Who was studied: 101 Italian individuals with suspected BAP1 tumor predisposition syndrome, enrolled at hospitals in Alessandria, Turin/Orbassano, Cuneo, Novara and Padua. They were selected for a family history of cancer plus a tumor of the syndrome's spectrum in the proband or a family member. Nine relatives of carriers were also tested. Exact calendar years are not stated.
• Exposure: Inherited (germline) variants in the BAP1 gene, detected in blood DNA. Testing used Sanger sequencing in 98 patients and a gene panel in 3, plus MLPA for deletions. Tumor tissue from carriers was then examined for loss of BAP1. Asbestos exposure of the patients was not assessed or reported in this article.
• Main results:
  • Seven of the 101 tested patients carried a germline BAP1 pathogenic variant: prevalence 6.9% (7/101), 95% CI 2.8 to 13.8.
  • Six different variants were found among the carriers: two nonsense, three splicing and one frameshift.
  • Germline MLPA found no deletions or duplications of BAP1.
  • One variant was new: c.605G>A p.Trp202*, found in proband MM981, who had multiple cutaneous melanomas and prostate cancer.
  • Cascade testing was done on 9 relatives of carriers.
  • Four relatives found to carry a variant were healthy when tested. At follow-up, three had been diagnosed with tumors of the syndrome's spectrum; one, a 23-year-old, was still healthy.
  • In proband MPM_HO1901 (II-3), the pleural mesothelioma carried the germline variant at a variant allele frequency of 89%. The authors considered this consistent with complete loss of the normal copy.
  • Some tumors in carriers retained a normal (wild-type) BAP1 copy. The renal cell carcinoma of proband MPM_HO1901 (II-3) is one example; the authors said it might not have been caused by the syndrome, at least at its start.
  • BAP1 protein was absent in the tumor cells of a meningioma in a carrier from family A.
  • No tumor sample carried somatic alterations in other cancer driver genes besides BAP1.
  • Seven mesothelioma patients carried germline BAP1 variants (six pleural, one peritoneal, per Table 3). The authors classed five as long-term survivors, compared with a mean survival of 9 to 17 months for pleural mesothelioma taken from another source. Recorded survival ranged from 4 months (sarcomatoid) to 108 months.
  • An MSH6 variant found in tumors of the MPM_HO1901 proband and her brother was judged benign by the authors.
• The authors' conclusion: The authors concluded that BAP1 carriers need an appropriate surveillance program, including healthy relatives carrying a variant. They also recommended confirming loss of both BAP1 copies in tumor tissue before enrolling patients in precision-medicine trials.
• Limitations the authors state:
  • The authors did not perform whole-genome analysis or use techniques able to detect complex rearrangements.
  • Because of technical limits and tumor heterogeneity, the authors could not rule out complete loss of both BAP1 copies in some tumors.
  • DNA from the lung adenocarcinoma specimens was partly degraded, so those results could not be adequately interpreted.
  • Immunohistochemistry on the deceased brother's (II-2) tissue failed, likely because of poor specimen condition.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, Tumor Suppressor Gene, BAP1 Tumor Predisposition Syndrome, Mesothelioma, Carcinoma, Next-Generation Sequencing (NGS).

Related studies

• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases — K. Rai, R. Pilarski, et al. (2016)
• Histologically Diverse BAP1-Deficient Melanocytic Tumors in a Patient With BAP1 Tumor Predisposition Syndrome — A. Louw, J. Creaney, et al. (2020)
• Malignant Peripheral Nerve Sheath Tumor in a Patient With BAP1 Tumor Predisposition Syndrome — M.C. Kaszuba, J.S. Pulido, et al. (2018)
• Post-thoracotomy neuralgic amyotrophy in a patient with BAP1 tumor predisposition syndrome: Multimodality longitudinal follow-up — N. Jazebi, N. Dargah-Zada, et al. (2021)

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