Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations

Our plain-English summary of Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations, by M.G. Zauderer, G. Jayakumaran, M. DuBoff, et al (Journal of Thoracic Oncology, 2019).

The study

• Authors: M.G. Zauderer, G. Jayakumaran, M. DuBoff, L. Zhang, J.H. Francis, D.H. Abramson, A. Cercek, G.M. Nash, A. Shoushtari, P. Chapman, S. D'Angelo, A.G. Arnold, B. Siegel, M.H. Fleischut, A. Ni, A. Rimner, V.W. Rusch, P.S. Adusumilli, W. Travis, J.L. Sauter, A. Zehir, D. Mandelker, M. Ladanyi, M. Robson
• Journal: Journal of Thoracic Oncology
• Published: 2019;14(11):1989-1994
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown.

Methods: We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation.

Results: Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1).

Conclusions: Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This brief report described a prospective study at Memorial Sloan Kettering Cancer Center in New York. Between March 2013 and October 2016, consecutive patients treated for mesothelioma, uveal melanoma or choroidal nevus (both eye conditions) were offered blood testing for inherited BAP1 gene mutations, regardless of family or asbestos history. Samples from 180 of 183 participants were tested, and 38% of participants reported known classic asbestos exposure. Five samples carried a mutation judged pathogenic or likely pathogenic. All five came from patients with mesothelioma, 5 of 113 or 4.4% (95% confidence interval 1.1 to 11.1), and none from the eye-condition groups. The authors' screening criteria flagged 108 patients as possible carriers, including all five. The probability that the criteria enriched for mutations by chance was 0.16. Among pleural mesothelioma patients, the 4 carriers were more often stage IV at diagnosis and tended to be younger. Their survival was better, but the difference was not statistically significant. The authors concluded the mutation is infrequent in mesothelioma. They noted the patients were mostly White.

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: Prospective clinical trial estimating the prevalence of germline BAP1 mutations in unselected (consecutive) patients and testing proposed screening criteria (brief report)
• Who was studied: 183 consecutive patients receiving care at Memorial Sloan Kettering Cancer Center, New York, between March 2013 and October 2016 for mesothelioma (115: 90 pleural, 25 peritoneal), uveal melanoma (27 primary, 20 metastatic) or choroidal nevus (21). Samples from 180 were analyzed. Most were White and non-Hispanic, and more were male (106) than female (77).
• Exposure: The main factor studied was inherited (germline) BAP1 mutation, detected by a 410-gene sequencing test of blood. Asbestos exposure, military service and smoking were recorded by questionnaire. 70 of 183 participants (38%) reported known classic asbestos exposure. No fiber types were specified.
• Main results:
  • Of 180 tested samples, 10 (5.6%) had a germline BAP1 mutation. 5 of these were considered pathogenic or likely pathogenic, giving a prevalence of 2.8% (95% CI 1.2-6.3) across all tested patients.
  • Among patients with mesothelioma, 5 of 113 had a pathogenic variant, a prevalence of 4.4% (95% CI 1.1-11.1).
  • Pleural mesothelioma: 4 of 88, 4.5% (95% CI 1.8-11.1). Peritoneal mesothelioma: 1 of 25, 4.0% (95% CI 0.2-19.5).
  • No pathogenic BAP1 mutations were found in patients with uveal melanoma or choroidal nevus.
  • All patients with pathogenic BAP1 alterations were among those flagged by the screening criteria (5 of 108 flagged patients, 4.6%, 95% CI 2.0-10.4). The probability that the criteria enriched for pathogenic variants by chance was 0.16.
  • Several patients without germline BAP1 mutations had features suggesting a heritable disorder, including 3 with mesothelioma and a family history of mesothelioma, and one with both pleural mesothelioma and uveal melanoma.
  • In pleural mesothelioma, stage IV disease at diagnosis was found in 3 of 4 (75%) BAP1 carriers versus 10 of 84 (12%) non-carriers (p = 0.01). Median age at diagnosis was 53 versus 69 years (p = 0.09).
  • Pleural mesothelioma patients with a germline BAP1 mutation had better overall survival than those without, but this difference was not statistically significant (p = 0.10).
  • Reported classic occupational asbestos exposure among pleural mesothelioma patients: 1 of 4 (25%) carriers versus 52 of 83 (63%) non-carriers (p = 0.30).
• The authors' conclusion: The authors concluded that the frequency of germline BAP1 mutation is low among patients with mesothelioma, and that their screening criteria identified all carriers while flagging about 60% of patients. They suggested the criteria could be validated as testing guidelines. They also concluded that genetic factors in mesothelioma and uveal melanoma extend beyond BAP1.
• Limitations the authors state:
  • The patient population lacked diversity, which might limit how widely the findings apply.
  • The high rate of other cancers may reflect more intensive screening at a tertiary cancer center than is typical.
  • Other BAP1-associated cancers identified near the end of the study were not included.
  • The testing platform may have missed some large genomic events or microdeletions.
  • Small numbers of patients with peritoneal mesothelioma, uveal melanoma and choroidal nevus may explain the few or absent mutations in those groups.
  • Uptake of the follow-up identified genetic testing was modest. The authors suggested possible reasons including legal concerns related to asbestos litigation.

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 Tumor Predisposition Syndrome, Germline Mutation, BAP1, Mesothelioma, Occupational Exposure, Next-Generation Sequencing (NGS), confidence interval.

Related studies

• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation — C. Ribeiro, S. Campelos, et al. (2013)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist — L.M. Martorano, R.R. Winkelmann, et al. (2014)

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