Germline BAP1 mutations predispose also to multiple basal cell carcinomas

Our plain-English summary of Germline BAP1 mutations predispose also to multiple basal cell carcinomas, by A. de la Fouchardière, O. Cabaret, L. Savin, et al (Clinical Genetics, 2015).

The study

• Authors: A. de la Fouchardière, O. Cabaret, L. Savin, P. Combemale, H. Schvartz, C. Penet, V. Bonadona, N. Soufir, B. Bressac-de Paillerets
• Journal: Clinical Genetics
• Published: 2015;88(3):273-7
• Cited by: 82 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The BRCA1-associated protein 1 (BAP1) gene encodes a nuclear deubiquitin enzyme which acts as a tumour suppressor. Loss of function germline mutations of BAP1 have been associated with an enhanced risk of uveal and cutaneous melanomas, mesothelioma, clear cell renal cancer and atypical cutaneous melanocytic proliferations. In two independent BAP1 families, we noticed an unusual frequency of basal cell carcinomas (BCCs). Indeed, 19 BCCs were diagnosed in four patients, either of superficial (13/19) or nodular (6/19) subtype; they were all located in chronic sun-exposed areas (limbs, head or neck). Immunohistochemistry (IHC) identified in the 19 tumours, complete or partial loss of BAP1 protein nuclear expression, restricted to the BCC nests. A control study was conducted in 22 sporadic BCCs in 22 subjects under 65 without known associated BAP1 tumours: no loss of BAP1 expression was found. Overall, our observations suggest that BCCs are part of the BAP1 cancer syndrome, perhaps in relation with chronic sun exposure and melanocortin 1 receptor (MC1R) variants. In conclusion, cutaneous follow-up of BAP1 carriers should not only aim to detect melanocytic neoplasms but also BCCs.

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

In plain English

This French report described two unrelated families with inherited BAP1 gene mutations. BAP1 had earlier been identified as a gene predisposing to mesothelioma. Of 15 BAP1 families identified at two French hospitals, these two had members with multiple basal cell carcinomas (BCCs), a common skin cancer. Four patients had 19 BCCs, 13 superficial and 6 nodular, all showing signs of chronic sun damage. One of the four, a woman, later developed peritoneal mesothelioma. The article does not discuss asbestos exposure. A tissue stain showed loss of nuclear BAP1 in every tumour nest in 17 of the 19 tumours and in 50% of nests in the other 2. All 22 BCCs from 22 comparison patients without BAP1-related cancers stained normally. The three living patients tested all carried a red hair colour variant of the MC1R gene. The authors concluded that multiple BCCs are part of the BAP1 cancer syndrome and that the stain could serve as a prescreening test before gene sequencing. They noted the series was small and their full patient series had not been extensively screened for associated conditions.

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 series of two families with BAP1 germline mutations. Their basal cell carcinomas were tissue-stained (immunohistochemistry) and compared with 22 basal cell carcinomas from patients without BAP1-related cancers.
• Who was studied: 4 patients from 2 of 15 families with germline BAP1 mutations identified at Gustave Roussy and Bichat Hospital, France. Comparison group: 22 basal cell carcinomas diagnosed before age 65 in 22 patients aged 28 to 64 (median 57) with no history of BAP1-related cancers or Gorlin syndrome. No study dates are given.
• Exposure: Inherited (germline) BAP1 mutations: c.437+1G>A in family 1/D and c.660-11T>A in family 2/K. BAP1 was initially identified as a mesothelioma-predisposing gene. Chronic sun exposure and MC1R gene variants were also considered. Asbestos exposure was not studied or discussed.
• Main results:
  • In the 4 BAP1 mutation carriers, 19 basal cell carcinomas were studied: 13 superficial and 6 nodular.
  • All of the carriers' basal cell carcinomas showed mild to severe dermal elastosis, a known indicator of chronic sun exposure.
  • In the BAP1 mutation carriers, 17 of 19 basal cell carcinomas showed complete loss of nuclear BAP1 staining in all tumour nests.
  • In the BAP1 mutation carriers, the other 2 of 19 basal cell carcinomas showed partial loss of BAP1 staining, found in 50% of the tumour nests.
  • In the carriers' specimens, surrounding non-tumour cells (keratinocytes, endothelial cells, lymphocytes) kept BAP1 staining, serving as internal positive controls.
  • In all 22 comparison basal cell carcinomas, every tumour nest stained normally for nuclear BAP1.
  • In this small series, the authors reported 100% sensitivity and specificity for the stain as a prescreening test for BAP1 germline mutation.
  • All 3 living patients genotyped for MC1R carried a red hair colour (RHC) variant.
  • One patient (patient 4, a woman in family 2/K) had melanoma and atypical melanocytic lesions and subsequently developed peritoneal mesothelioma.
  • The carriers' basal cell carcinomas did not show aggressive features under the microscope or clinically.
• The authors' conclusion: The authors concluded that multiple basal cell carcinomas are part of the BAP1 cancer syndrome. They also concluded that BAP1 staining could be used as a prescreening test before BAP1 sequencing.
• Limitations the authors state:
  • The authors stated that no extensive phenotypic screening (examination for associated conditions) was done across their full series of patients.
  • The authors described the series as small.
  • The authors noted that basal cell carcinomas are the most common cancer type in Caucasian populations.

Topics

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

Related studies

• 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)
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• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos — G. Brandi, M. Deserti, et al. (2020)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)

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