A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma

Our plain-English summary of A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma, by K.A. Wadt, L.G. Aoude, P. Johansson, et al (Clinical Genetics, 2015).

The study

• Authors: K.A. Wadt, L.G. Aoude, P. Johansson, A. Solinas, A. Pritchard, O. Crainic, M.T. Andersen, J.F. Kiilgaard, S. Heegaard, L. Sunde, B. Federspiel, J. Madore, J.F. Thompson, S.W. McCarthy, A. Goodwin, H. Tsao, G. Jönsson, K. Busam, R. Gupta, J.M. Trent, A.M. Gerdes, K.M. Brown, R.A. Scolyer, N.K. Hayward
• Journal: Clinical Genetics
• Published: 2015;88(3):267-72
• Cited by: 77 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

In plain English

This short report described families with inherited (germline) BAP1 gene mutations, four not previously reported. Tumors in these families were mainly uveal (eye) melanoma, cutaneous (skin) melanoma and mesothelioma. The authors also found basal cell carcinoma (BCC), a common skin cancer, in carriers. Seven Danish carriers had BCC, one of them with 13 tumors. One BCC showed loss of the normal copy of BAP1. Three BCCs lacked BAP1 protein on staining, one from a person of unknown carrier status. None of 53 sporadic BCCs did. A skin melanoma, an atypical Spitzoid tumor and a peritoneal mesothelioma from the Family 2 proband lacked BAP1 staining. The same mutation, p.R60X, was found in three families. Two Danish families appeared to share it from a common ancestor; the mutation was estimated to have arisen 91 generations ago (90% CI: 20–254). It arose independently in the third. The authors proposed that BAP1 mutation carriers have an increased risk of BCC. They noted that BCC is common in Denmark and was absent from the non-Danish families. The article did not discuss asbestos exposure.

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: Short report: family (pedigree) study with genetic testing, haplotype analysis, loss of heterozygosity analysis and immunohistochemistry of tumors
• Who was studied: Members of families with germline BAP1 mutations (four new families plus a previously reported Danish family), referred to genetics clinics in Copenhagen, Denmark and Sydney, Australia; plus 53 sporadic BCCs used for comparison staining
• Exposure: Inherited (germline) BAP1 gene mutations, including the recurrent mutation p.R60X. No asbestos exposure was studied or reported.
• Main results:
  • Seven Danish BAP1 mutation carriers had basal cell carcinoma (BCC). One carrier had 13 tumors.
  • In the one BCC analysed for loss of heterozygosity (Family 3, II-7), the normal (wildtype) copy of BAP1 was lost.
  • Three BCCs (Family 3: IV-1; Family 4: II-4 and III-1) showed loss of BAP1 protein staining. It is unknown whether II-4 carries the mutation.
  • None of 53 sporadic BCCs showed loss of BAP1 protein expression.
  • The cutaneous melanoma, the mesothelioma (peritoneal) and the atypical Spitzoid tumor from the proband of Family 2 all lacked BAP1 staining.
  • Carriers in the two Danish families (Families 3 and 4) shared a stretch of DNA around BAP1, consistent with a haplotype from a common ancestor.
  • The p.R60X mutation in the Danish families was estimated to have arisen 91 generations ago (90% CI: 20–254).
  • In Family 5 the p.R60X mutation arose independently, because Family 5 did not share the Danish families' BAP1 haplotype.
  • In one family with several cancers of unknown primary site, a peritoneal mesothelioma with an unusual presentation was diagnosed only after death.
• The authors' conclusion: The authors proposed that BAP1 mutation carriers have an increased risk of basal cell carcinoma, adding it to the BAP1 tumor syndrome spectrum.
• Limitations the authors state:
  • BCC was seen only in the Danish families, not in the non-Danish families.
  • BCC is common in Denmark. In 2012 the age-standardized incidence was 187 per 100,000 in men and 176 per 100,000 in women.
  • One of the BCCs with loss of BAP1 staining came from a person whose carrier status is unknown.

Topics

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

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• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
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