CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma

Our plain-English summary of CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma, by M. Betti, A. Aspesi, A. Biasi, et al (Cancer Letters, 2016).

The study

• Authors: M. Betti, A. Aspesi, A. Biasi, E. Casalone, D. Ferrante, P. Ogliara, L.C. Gironi, R. Giorgione, P. Farinelli, F. Grosso, R. Libener, S. Rosato, D. Turchetti, A. Maffè, C. Casadio, V. Ascoli, C. Dianzani, E. Colombo, E. Piccolini, M. Pavesi, S. Miccoli, D. Mirabelli, C. Bracco, L. Righi, R. Boldorini, M. Papotti, G. Matullo, C. Magnani, B. Pasini, I. Dianzani
• Journal: Cancer Letters
• Published: 2016;378(2):120-30
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In plain English

The authors studied 40 Italian families with suspected inherited mesothelioma, melanoma or both (6 both, 23 melanoma only, 11 mesothelioma only). One member per family was to be tested for BAP1 and parts of five melanoma genes, including CDKN2A. Some tests were not done; for three patients with unavailable or scanty DNA, BAP1 was checked only by tissue protein staining. Of 12 mesothelioma patients, 10 had exposure information; all 10 had asbestos exposure, at work or at home. A woman with two skin melanomas, a meningioma and a pleural mesothelioma carried a protein-shortening BAP1 mutation; the authors described her as not heavily exposed to asbestos. In another family, a CDKN2A mutation was found in a woman with skin melanoma and her mother, who had melanoma, mesothelioma and 'low' asbestos exposure at work. Two other BAP1 changes were of uncertain significance and one likely neutral. Three families with both cancers had no mutation in the genes tested. The authors concluded that CDKN2A, like BAP1, could be involved in susceptibility to both cancers, and that larger studies should confirm this.

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: Genetic study of a series of families with suspected inherited cancer predisposition. One index patient per family (the proband) was planned for germline sequencing of BAP1 and of selected regions or variants of five melanoma genes, though some tests were not done. Mutation carriers had follow-up tumor and protein (immunohistochemistry) testing.
• Who was studied: 40 Italian families, all probands Caucasian of Italian ancestry: 6 families with both mesothelioma and melanoma, 23 with melanoma (without mesothelioma) and 11 with mesothelioma (without melanoma). Probands came from melanoma and mesothelioma databases at centers in Novara, Turin, Bologna, Reggio Emilia, Alessandria, Cuneo and Rome.
• Exposure: Inherited (germline) variants in BAP1 and in selected regions or variants of CDKN2A, CDK4, TERT, MITF and POT1. Asbestos exposure in mesothelioma probands was assessed by questionnaire or records: possible occupational exposure for four, para-occupational or household exposure for five, and both for one. Fiber types are not reported. UV exposure and skin type were assessed in melanoma probands.
• Main results:
  • Not every proband received every test. Table 1 marks some tests as not done. For three mesothelioma probands (IDs 31, 37, 39), germline DNA was not available or very scanty, and BAP1 was assessed by immunohistochemistry, which showed normal nuclear expression. One of them (ID31) still had CDKN2A and CDK4 results.
  • Asbestos exposure information was available for 10 of 12 mesothelioma probands, and all 10 showed asbestos exposure.
  • Family ID5: the proband carried a heterozygous BAP1 nonsense mutation (c.1153C > T, p.Arg385*). The proband developed two cutaneous melanomas (at 53 and 57 years), a meningioma (37 years) and an epithelioid pleural mesothelioma (53 years). Both the melanoma and the mesothelioma showed no BAP1 nuclear expression.
  • The authors reported that the ID5 proband was not heavily exposed to asbestos.
  • Family ID3: a recurrent pathogenic CDKN2A germline mutation (c.301G > T, p.Gly101Trp) was found. Carriers were the proband, who had cutaneous melanoma, and her mother, who had both cutaneous melanoma and mesothelioma.
  • The ID3 proband's mother's asbestos exposure at work was rated 'low exposure', a category covering occupational exposures outside industries that used asbestos directly as a raw material.
  • The BAP1 missense variant p.Asp567Ala (family ID16, melanoma only) was classed as a variant of unknown significance.
  • The 19 bp BAP1 promoter duplication in family ID4 was considered a variant of unknown significance.
  • The 5 bp BAP1 promoter duplication (c.-594dupCCCGT) in family ID16 was judged a likely neutral variant.
  • Three other families with both mesothelioma and melanoma (IDs 1, 2 and 6) had no germline mutations in any of the six genes tested.
• The authors' conclusion: The authors concluded that CDKN2A, in addition to BAP1, could be involved in susceptibility to melanoma and mesothelioma, and that their study suggests for the first time that CDKN2A may predispose to mesothelioma.
• Limitations the authors state:
  • The authors' hypothesis needs to be confirmed in a larger series of patients.
  • The authors could not exclude that the mesothelioma in the CDKN2A family occurred independently in a person otherwise predisposed to melanoma.
  • Studies of familial predisposition may over-represent long survivors.
  • The disease-causing potential of missense variants could not be settled without a functional assay.
  • For family ID4, the promoter variant could not be traced through the family because key relatives were not available.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: CDKN2A, BAP1, Germline Mutation, Mesothelioma, Carcinogenic, Carcinogenesis, Malignant Mesothelioma.

Related studies

• 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)
• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)

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