Mesothelioma families without inheritance of a BAP1 predisposing mutation

Our plain-English summary of Mesothelioma families without inheritance of a BAP1 predisposing mutation, by V. Ascoli, I. Cozzi, S. Vatrano, et al (Cancer Genetics, 2016).

The study

• Authors: V. Ascoli, I. Cozzi, S. Vatrano, S. Izzo, J. Giorcelli, E. Romeo, C. Carnovale-Scalzo, L.R. Grillo, F. Facciolo, P. Visca, M. Papotti, L. Righi
• Journal: Cancer Genetics
• Published: 2016;209(9):381-387
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Familial malignant mesothelioma clusters are ideal candidates to explore BAP1 genomic status as a predisposing risk factor. We report data on BAP1 analysis in four families with multiple mesothelioma cases to investigate possible BAP1 alterations associated with an inherited cancer syndrome. We also recorded family history of cancer and assessed asbestos exposure. By genomic direct sequencing, we found no evidence of a BAP1 germline mutation in tumor DNA samples (one mesothelioma per family: n = 3 epithelioid; n = 1 biphasic). On the other hand, we identified a novel BAP1 somatic alteration (c.329_335delinsTC) in exon 5 (n = 1 biphasic), and we hypothesized the occurrence of somatic inactivating events not identifiable by sequencing in the other cases (n = 3 epithelioid), as demonstrated by the loss of nuclear BAP1 immunostaining. History of other cancers was in sites not typical of the BAP1 cancer syndrome. Asbestos exposure was occupational (n = 2 clusters), household (n = 1), and unknown (n = 1). These family units without inheritance of a BAP1 predisposing mutation expand the number of unmutated germline BAP1 families with multiple mesothelioma cases. This suggests that besides the exposure to asbestos other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in BAP1-unmutated families.

Copyright © 2016 Elsevier Inc. All rights reserved.

In plain English

This study looked at the BAP1 gene in four Italian families in which two or more blood relatives had malignant mesothelioma. Inherited BAP1 mutations are linked to a hereditary cancer syndrome. The families were found through a regional section of the Italian Mesothelioma Registry and a pathology archive. Blood samples were not available, so the authors sequenced BAP1 in stored tumor tissue from one index case per family (three epithelioid, one biphasic). They also stained tumors from 8 of the 9 affected relatives for BAP1 protein. Interviews showed asbestos exposure was occupational in two families, household in one and unknown in one. No inherited BAP1 mutation was found. In the biphasic case, a previously unreported BAP1 change was present in the tumor but not in normal tissue, meaning it arose in the tumor. Epithelioid tumors had lost BAP1 staining in the cell nucleus. Other cancers in the families were not of types typical of the BAP1 syndrome. The authors concluded that, besides asbestos exposure, currently unknown genetic or epigenetic factors may explain the high mesothelioma rate in such families.

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: Laboratory genetic and tissue-staining (immunohistochemistry) study of four families with multiple mesothelioma cases (family case series)
• Who was studied: Four families (C, D, G and O) from Italy with at least two first-degree relatives with malignant mesothelioma, 9 affected relatives in total. The families were identified through a regional section of the Italian Mesothelioma Registry and a pathology-based archive. One affected relative (O-II-3) had peritoneal mesothelioma.
• Exposure: Asbestos exposure, assessed by interviewing patients and/or next of kin with a standard questionnaire: occupational in 2 families, household in 1, unknown in 1. No fiber types or doses are given. The main factor studied was BAP1 gene status.
• Main results:
  • No BAP1 germline (inherited) mutation was found in the tumor DNA of the four index cases (one per family: 3 epithelioid, 1 biphasic).
  • In the biphasic index case (D-II-4), a complex BAP1 insertion/deletion in exon 5 (c.329_335delinsTC) was found in the tumor. Normal tissue from this case lacked it, indicating it arose in the tumor (somatic) rather than being inherited. The authors state it had not been previously reported.
  • On BAP1 staining, all epithelioid mesotheliomas, and the epithelioid cells of the biphasic tumor, showed complete loss of nuclear BAP1. Nuclear BAP1 was retained only in the sarcomatoid mesothelioma (G-II-8) and in sarcomatoid cells of the biphasic tumor. The authors suggested the loss may reflect somatic BAP1 changes not detectable by sequencing.
  • Personal or family history of other cancers was positive in 3 families (stomach, pancreas, lung, prostate, colon). These were not sites typical of the BAP1 cancer syndrome.
• The authors' conclusion: The authors concluded that these families add to the number of mesothelioma families without an inherited BAP1 mutation. They suggested that, besides asbestos exposure, other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in such families.
• Limitations the authors state:
  • Large BAP1 deletions, which Sanger sequencing cannot detect, could not be excluded.
  • There was not enough tumor DNA for a comprehensive analysis of BAP1 gene alterations.
  • Blood samples were unavailable and only limited stored tissue specimens could be used.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, BAP1, Malignant Mesothelioma, Asbestos Exposure, Germline Mutation, Epithelioid, Biphasic Mesothelioma, BAP1 Tumor Predisposition Syndrome.

Related studies

• An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation — M. Cheung, Y. Kadariya, et al. (2015)
• Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors — M. Cheung, Y. Kadariya, et al. (2021)
• Tumours associated with BAP1 mutations — R. Murali, T. Wiesner, et al. (2013)
• BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma — H. Alakus, S.E. Yost, et al. (2015)
• Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases — K. Rai, R. Pilarski, et al. (2016)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)

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