A population-based analysis of germline BAP1 mutations in melanoma

Our plain-English summary of A population-based analysis of germline BAP1 mutations in melanoma, by S.J. O'Shea, C.D. Robles-Espinoza, L. McLellan, et al (Human Molecular Genetics, 2017).

The study

• Authors: S.J. O'Shea, C.D. Robles-Espinoza, L. McLellan, J. Harrigan, X. Jacq, J. Hewinson, V. Iyer, W. Merchant, F. Elliott, M. Harland, D.T. Bishop, J.A. Newton-Bishop, D.J. Adams
• Journal: Human Molecular Genetics
• Published: 2017;26(4):717-728
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma.

© The Author 2017. Published by Oxford University Press.

In plain English

This UK study looked at inherited (germline) changes in the BAP1 gene in people with skin melanoma. The authors sequenced BAP1 in 1,977 melanoma patients from the Leeds Melanoma Case-Control Study and in 754 controls. They tested variants in laboratory enzyme assays, reviewed family cancer histories and examined tumour tissue. They found 30 variants, 27 of them rare. Three clear loss-of-function variants were found in 3 of 1,977 cases and 0 of 754 controls. In those three families, relatives had BAP1-linked cancers, including mesothelioma in two families, but no uveal melanoma. Nine cases were grouped as 'predicted deleterious': these three, plus six whose variants computer programs predicted harmful but that showed no detected change in enzyme activity. Of 7 cases with mesothelioma in themselves or their family, 3 were among these nine (odds ratio 233, 95% CI 26.7 to 1660.1, versus cases with no variant). The authors noted that these figures rest on small numbers. The article does not describe any asbestos exposure. The authors concluded that loss-of-function or predicted harmful BAP1 variants were rare, in under 1% of cases.

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: Case-control genetic sequencing study, with laboratory enzyme (deubiquitinase) assays, family history (pedigree) analysis and review of tumour tissue
• Who was studied: 1,977 melanoma cases and 754 controls. The cases and 488 of the controls came from the Leeds Melanoma Case-Control Study, which recruited mainly from Yorkshire, UK. A further 266 controls came from Wellcome Trust Case Control Consortium samples. Recruitment dates are not given in this text.
• Exposure: Inherited (germline) variants in the BAP1 gene, found by targeted sequencing. The article does not describe asbestos or any fiber exposure.
• Main results:
  • Sequencing found 30 BAP1 variants in total, of which 27 were rare.
  • Clear loss-of-function (group 1) variants were found in 3 of 1,977 cases and 0 of 754 controls.
  • Variants in groups 1, 2 and 3 were found in 23 cases (1.2%). Five controls (0.7%) had variants of the same severity. The authors reported this difference as not statistically significant (P = 0.294).
  • One missense variant found in a case (S98R) completely abolished BAP1 deubiquitinase activity in the laboratory assay.
  • The 'predicted deleterious' group of nine cases combined the three confirmed loss-of-function carriers with six carriers of variants predicted to be hazardous by the SIFT and/or PolyPhen-2 computer programs. No alteration of deubiquitinase function was detected for those six variants.
  • In family 1 (frameshift variant), a second-degree relative had mesothelioma. In family 3 (splice acceptor variant), one individual had mesothelioma, and another had a malignant blue naevus and meningioma.
  • Mesothelioma in the patient or family occurred in 3 of the 9 cases with predicted deleterious variants and in 4 of the 1,868 cases with no variant. Compared with cases with no variant, the odds ratio was 233 (95% CI 26.7 to 1660.1), P = 0.000003.
  • Meningioma in the patient or family was also associated with carrying a predicted deleterious variant compared with no variant: odds ratio 58.3 (95% CI 1.1 to 670.5), P = 0.02.
  • No case with a predicted deleterious variant had a personal or family history of ocular melanoma.
  • Two of the three cases with loss-of-function variants had melanomas with BAP1-like tissue features. None of the other six cases with predicted deleterious variants had such features.
• The authors' conclusion: The authors concluded that BAP1 variants that were loss-of-function, or predicted by SIFT and PolyPhen-2 to be damaging or deleterious, were rare. Counting all nine such cases, they made up under 1% of the melanoma cases, and complete loss-of-function variants were found in 0.2%. The authors also concluded that, without a family history of cancers such as mesothelioma or meningioma, BAP1-like tissue changes are a poor predictor of a germline BAP1 mutation.
• Limitations the authors state:
  • The enzyme assay detects only large effects, so subtle changes in BAP1 activity might be missed.
  • There were very few cases of mesothelioma or meningioma in the cohort, so these associations rest on small numbers.
  • Family cancer histories were self-reported, and the detail provided varied. Diagnoses could be confirmed by pathology only where family members were also recruited.
  • Central pathology review was available for just over one third of the probands with a family history (713 of 1,977).
  • Other ways the variants might affect BAP1, such as protein turnover or localisation, were not assessed.

Topics

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

Related studies

• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma — K.G. Ewens, E. Lalonde, et al. (2018)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• Clinical Implications of Real-time Integrative Sequencing in Management of Patients With Suspected Germline BAP1 Mutations — S. Sengupta, A.C. Weyand, et al. (2019)
• Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation — C. Ribeiro, S. Campelos, et al. (2013)

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