Tumours associated with BAP1 mutations

Our plain-English summary of Tumours associated with BAP1 mutations, by R. Murali, T. Wiesner, R.A. Scolyer (Pathology, 2013).

The study

• Authors: R. Murali, T. Wiesner, R.A. Scolyer
• Journal: Pathology
• Published: 2013;45(2):116-26
• Type of article: Review
• Cited by: 225 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

BAP1 (BRCA1-Associated Protein 1) was initially identified as a protein that binds to BRCA1. BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway. Germline mutations of BAP1 confer increased susceptibility for the development of several tumours, including uveal melanoma, epithelioid atypical Spitz tumours, cutaneous melanoma, and mesothelioma. However, the complete tumour spectrum associated with germline BAP1 mutations is not yet known. Somatic BAP1 mutations are seen in cutaneous melanocytic tumours (epithelioid atypical Spitz tumours and melanoma), uveal melanoma, mesothelioma, clear cell renal cell carcinoma, and other tumours. Here, we review the current state of knowledge about the functional roles of BAP1, and summarise data on tumours associated with BAP1 mutations. Awareness of these tumours will help pathologists and clinicians to identify patients with a high likelihood of harbouring germline or somatic BAP1 mutations. We recommend that pathologists consider testing for BAP1 mutations in epithelioid atypical Spitz tumours and uveal melanomas, or when other BAP1-associated tumours occur in individual patients. Tumour tissues may be screened for BAP1 mutations/loss/inactivation by immunohistochemistry (IHC) (demonstrated by loss of nuclear staining in tumour cells). Confirmatory sequencing may be considered in tumours that exhibit BAP1 loss by IHC and in those with equivocal IHC results. If a BAP1 mutation is confirmed in a tumour, the patient's treating physician should be informed of the possibility of a BAP1 germline mutation, so they can consider whether genetic counselling and further testing of the patient and investigation of their family is appropriate. Recognition and evaluation of larger numbers of BAP1-associated tumours will also be necessary to facilitate identification of additional distinct clinico-pathological characteristics or other genotype-phenotype correlations that may have prognostic and management implications.

In plain English

This review, not a new study, summarised published research on tumours linked to inherited (germline) and acquired (somatic) BAP1 gene mutations, including uveal melanoma, atypical Spitz skin tumours, cutaneous melanoma, mesothelioma and kidney cancer. On mesothelioma, it described a study by Testa and colleagues that found germline BAP1 mutations in all affected members of two families in which several members developed mesothelioma, but not in unaffected relatives. None had occupational asbestos exposure, but all had lived in homes containing asbestos. That group also found germline mutations in two of 26 people with sporadic mesothelioma. Bott and colleagues found somatic BAP1 mutations in 20% (24/121) of mesotheliomas. Citing that study, the review stated that there does not appear to be an association between BAP1 mutations and asbestos exposure. Another study found mutations in 13 of 16 pure epithelioid mesotheliomas, compared with 1 of 3 biphasic and 0 of 4 sarcomatoid tumours. The authors concluded that germline BAP1 mutations confer susceptibility to a tumour predisposition syndrome, and that environmental influences likely also modify risk. They noted that in many reports, other inherited genes or coincidental tumours could not be excluded.

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: Narrative review of published literature on BAP1 function and BAP1-associated tumours
• Who was studied: No new patients. The review drew on published reports of families and patients with germline BAP1 mutations, and on published series of tumours tested for somatic BAP1 mutations (uveal melanoma, skin melanocytic tumours, mesothelioma, renal cell carcinoma and other cancers).
• Exposure: The main subject was germline and somatic BAP1 gene mutations. Asbestos exposure was discussed only within the mesothelioma studies reviewed, and no fiber types were named. In the Testa families there was no occupational exposure, but all affected members had lived in homes containing asbestos. In the Wiesner family there was no history of significant asbestos exposure.
• Main results:
  • Reviewed study (Testa and colleagues): in two families in which multiple members developed mesotheliomas, germline BAP1 mutations were found in all affected members but not in unaffected relatives.
  • Reviewed study (Testa and colleagues): germline BAP1 mutations were found in 2 of 26 individuals with sporadic mesothelioma.
  • Reviewed study (Wiesner et al.): in one family, four members developed mesotheliomas (2 pleural, 1 peritoneal, 1 peritoneal and pleural) and carried a germline BAP1 mutation, with no history of significant asbestos exposure. One patient with pleural mesothelioma died within 2 years of diagnosis, and the other three were long-term survivors.
  • Reviewed study (Bott and colleagues): somatic BAP1 mutations were found in 20% (24/121) of mesotheliomas.
  • The review stated, citing Bott and colleagues, that there does not appear to be an association between BAP1 mutations and asbestos exposure.
  • Reviewed study (Yoshikawa et al.): BAP1 gene alterations were found in 61% of mesotheliomas. BAP1 mutations were significantly more common in pure epithelioid mesotheliomas (13/16 cases) than in biphasic (1/3 cases) or sarcomatoid tumours (0/4 cases). Bott et al. found no association between somatic BAP1 mutation and cell type.
  • Reviewed study (Harbour and colleagues): BAP1 mutations were present in 27 of 57 (47%) uveal melanomas, and in 26 of 31 (84%) metastasising uveal melanomas.
• The authors' conclusion: The authors concluded that germline BAP1 mutations confer susceptibility to several tumours that form a tumour predisposition syndrome. They considered it likely that environmental influences also modify the risk of these tumours, and stated that pathologists should be aware of BAP1-associated tumours and that identifying them should prompt BAP1 testing.
• Limitations the authors state:
  • In many reports of tumours associated with germline BAP1 mutations, other co-segregating cancer predisposition genes or coincidental sporadic tumours could not be excluded.
  • The longer survival seen in the Wiesner family's mesothelioma patients may reflect lead-time bias from earlier diagnosis rather than less aggressive disease. Further study is required.
  • Larger studies, including correlation with clinical and pathological features, are needed to establish associations with BAP1 alterations in mesothelioma.
  • BAP1 immunohistochemistry can give falsely negative results from technical problems, and some missense variants may still show detectable protein despite an inactivating mutation.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, Epithelioid, Mesothelioma, BAP1 Tumor Predisposition Syndrome, Carcinoma, Immunohistochemistry, Treating Physician.

Related studies

• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma — H. Alakus, S.E. Yost, et al. (2015)
• Mesothelioma families without inheritance of a BAP1 predisposing mutation — V. Ascoli, I. Cozzi, et al. (2016)
• A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma — K.A. Wadt, L.G. Aoude, et al. (2015)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist — L.M. Martorano, R.R. Winkelmann, et al. (2014)

Browse more research in Pathology, or return to medical research.