BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs

Our plain-English summary of BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs, by M. Carbone, L.K. Ferris, F. Baumann, et al (Journal of Translational Medicine, 2012).

The study

• Authors: M. Carbone, L.K. Ferris, F. Baumann, A. Napolitano, C.A. Lum, E.G. Flores, G. Gaudino, A. Powers, P. Bryant-Greenwood, T. Krausz, E. Hyjek, R. Tate, J. Friedberg, T. Weigel, H.I. Pass, H. Yang
• Journal: Journal of Translational Medicine
• Published: 2012;10:179
• Cited by: 244 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma.

Methods: Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson χ2 test or two-tailed Fisher's exact test).

Results: Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p ≤ 0.001).

Conclusions: Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.

In plain English

This study looked at families carrying inherited (germline) changes in the BAP1 gene. The article does not discuss asbestos. First, a dermatologist examined skin lesions from five members of family L and seven members of family W. Four of the five L members (80%) and four of the seven W members (57%) had one or more unusual skin tumors, which the authors named MBAITs. The patients said these lesions looked and behaved as benign. Second, the authors pooled data on 118 people from seven families described in published studies, comparing 63 mutation carriers with 55 relatives without the mutation. At least one cancer was found in 63.5% of carriers and 9.1% of non-carriers (odds ratio 17.39, 95% CI 6.07-49.83). Malignant mesothelioma occurred in 13 of 62 carriers with usable data (21.0%) and in none of the 55 non-carriers. Lung, breast and renal cancer rates did not differ significantly. The authors concluded that germline BAP1 mutations are associated with a new cancer syndrome. They noted that more carriers must be studied before other cancers can be linked to it or ruled out.

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: Clinical and pathological study of skin lesions in members of two families, combined with a pooled analysis of individual data from published BAP1-mutated families (the authors call it a meta-analysis), comparing mutation carriers with non-carriers from the same families
• Who was studied: Skin tumors from 5 members of family L and 7 members of family W. These are two unrelated families the authors had previously reported to carry germline BAP1 mutations with increased risk of malignant mesothelioma. The pooled analysis covered 118 individuals from seven families, drawn from four studies published between August 2011 and April 2012 plus the present findings: 63 BAP1-mutated and 55 non-mutated.
• Exposure: Germline (inherited) BAP1 mutations, detected by sequencing DNA from blood. Family L carried p.Gln684* and family W carried p.Pro147fs*48. The article does not address asbestos or other fiber exposure.
• Main results:
  • Family L: of 5 members studied, 4 (80%) had one or more MBAITs and 4 (80%) carried the BAP1 mutation. The one member without MBAITs (L-IV-5) was not mutated.
  • Family W: all 7 members studied carried the BAP1 mutation, and 4 (57%) had one or more MBAITs.
  • Patients reported that all MBAITs looked and behaved as benign.
  • Pooled analysis: at least one cancer in 40 of 63 carriers (63.5%) versus 5 of 55 non-carriers (9.1%), p less than 0.001.
  • Odds ratio for any cancer, carriers versus non-carriers: 17.39 (95% CI 6.07-49.83).
  • Malignant mesothelioma: 13 of the 62 carriers with informative data (21.0%) versus 0 of 55 non-carriers (0.0%), p less than 0.001. One carrier had cancer of unknown origin. The article does not specify the site of the disease (pleural or peritoneal).
  • Uveal melanoma: 11 of 62 informative carriers (17.7%) versus 0 non-carriers, p = 0.001. Cutaneous melanoma: 8 of 62 informative carriers (12.9%) versus 0 non-carriers, p = 0.007.
  • MBAITs: 24 of 36 carriers (66.7%) versus 0 of 12 non-carriers, p less than 0.001. This was calculated only in individuals from the present study and two of the other studies.
  • No significant difference between carriers and non-carriers in other cancers. Lung: 3 (4.8%) vs 0, p = 0.246. Breast, women only: 3 (7.9%) vs 1 (4.1%), p = 0.621. Renal: 2 (3.3%) vs 0, p = 0.497.
  • BRAFV600E mutations were found in all nine diagnosed MBAITs that were genotyped.
• The authors' conclusion: The authors concluded that germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly other cancers. In the discussion they state that these mutations cause an autosomal dominant hereditary cancer syndrome. They proposed MBAITs as a marker for identifying possible carriers.
• Limitations the authors state:
  • More BAP1-mutant family members need to be studied before links to additional cancers can be ruled out, because carcinomas are relatively common in the general population.
  • Because numbers for each cancer site were very small, an odds ratio was calculated only for overall cancer risk.
  • The authors had no explanation for the higher proportion of women among carriers (63.3% vs 43.6%, p = 0.034).

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1 Tumor Predisposition Syndrome, Mesothelioma, BAP1, Tumor Suppressor Gene, Neoplasm, Meta-Analysis.

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