Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer

Our plain-English summary of Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer, by J.A. Ohar, M. Cheung, J. Talarchek, et al (Cancer Research, 2016).

The study

• Authors: J.A. Ohar, M. Cheung, J. Talarchek, S.E. Howard, T.D. Howard, M. Hesdorffer, H. Peng, F.J. Rauscher, J.R. Testa
• Journal: Cancer Research
• Published: 2016;76(2):206-15
• Cited by: 79 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.

©2015 American Association for Cancer Research.

In plain English

This genetic study looked for inherited (germline) mutations in the BAP1 gene among people with a history of asbestos exposure. The authors tested 150 patients with malignant mesothelioma who had a personal or family history of cancer. They also tested two control groups. One had 50 asbestos-exposed people with a family history of cancers other than mesothelioma. The other had 153 asbestos-exposed people with mild asbestosis and/or pleural plaques and no family history of cancer. BAP1 mutations were found in 9 of the 150 mesothelioma patients (6%) and in none of the controls. In laboratory tests, the three missense mutations showed reduced enzyme activity. Five of the 9 carriers had peritoneal mesothelioma, compared with 25 of 141 non-carriers. Carriers were diagnosed at a mean age of 57.9 years, compared with 68.2 years for non-carriers. Among the 7 deceased mesothelioma patients in carrier families, median survival was 60 months, against 17 months for people without a mutation. Differences in latency, gender and cancer score were not statistically significant. The authors concluded that mesothelioma patients with a family history of cancer should be considered for BAP1 genetic testing.

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 case-control study: sequencing of the BAP1 gene in blood (germline) DNA of asbestos-exposed mesothelioma cases and asbestos-exposed controls, with laboratory tests of how the mutations affect the protein.
• Who was studied: 150 malignant mesothelioma patients with asbestos exposure and a personal or family history of cancer (selected with a family 'cancer signal' score). 50 asbestos-exposed controls with a high family cancer score but no mesothelioma in themselves or their families. 153 asbestos-exposed controls with mild asbestosis and/or pleural plaques and no personal or family cancer history. Participants were identified through health care providers, the Mesothelioma Applied Research Foundation, or independent medical-legal evaluations. Pathology reports came from laboratories in the United States or Canada. Study dates are not given.
• Exposure: All participants had a history of asbestos exposure. The article does not specify fiber types, products, jobs or doses. The factor actually compared between groups was inherited BAP1 gene mutation.
• Main results:
  • Germline BAP1 mutations were found in 9 of 150 mesothelioma cases (6%) with a family history of cancer. None were found in either control group (50 and 153 people).
  • Of the 9 mutations, 3 were missense mutations, 2 were splice site mutations and 4 were insertions/deletions. Two apparently unrelated cases shared the same mutation (c.1717delC).
  • In a laboratory assay, the enzyme activity of each of the three missense mutant BAP1 proteins was reproducibly lower than that of normal BAP1.
  • Among the 9 mutation carriers, 5 (55.6%) had peritoneal and 4 (44.4%) had thoracic mesothelioma. Table 1 marks the location difference from non-carriers as p less than 0.05.
  • Among mesothelioma cases without a BAP1 mutation, 116 (82.3%) had thoracic and 25 (17.7%) had peritoneal tumors.
  • Mean age at mesothelioma diagnosis was 57.9 years for the 9 carrier index cases and 68.2 years for the 141 non-carriers. Table 1 marks this difference as p less than 0.01. Not all carriers were young: two were diagnosed at 67 and 81.
  • There was no significant difference between carriers and non-carriers in cancer signal score, gender or latency.
  • Among the 11 mesothelioma patients in the 9 carrier families, the 7 who had died had a median survival of 60 months after diagnosis. Median survival among people without a BAP1 mutation was 17 months. No statistical test is reported for this comparison.
  • In the 9 carrier families, 11 BAP1-syndrome-type tumors were identified: 4 kidney (renal cell) cancers, 3 mesotheliomas, 2 cutaneous melanomas and 2 uveal melanomas.
  • Two mesothelioma cases without a BAP1 mutation each had two siblings with mesothelioma. The authors noted that multiple mesotheliomas in a family need not be due to an inherited BAP1 mutation.
• The authors' conclusion: The authors concluded that their findings suggest mesothelioma patients with a family history of cancer should be considered for BAP1 genetic testing, to identify people who might benefit from screening and monitoring for early detection.
• Limitations the authors state:
  • Detailed skin examinations of the carrier families were not available, so atypical skin melanocytic tumors linked to the BAP1 syndrome could not be ruled out.
  • Reported gastric (stomach) cancers in carrier families could not be confirmed by pathology, so their true type is uncertain.
  • Because lung and breast cancers are so common, the authors said it is too early to know whether they belong to the BAP1 syndrome.

Topics

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

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

Related studies

• Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma — J. Xu, Y. Kadariya, et al. (2014)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Detecting germline BAP1 mutations in patients with peritoneal mesothelioma: benefits to patient and family members — M. Kittaneh, C. Berkelhammer (2018)
• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)
• Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation — C. Ribeiro, S. Campelos, et al. (2013)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)

Browse more research in Cancer Research, or return to medical research.