Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma

Our plain-English summary of Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma, by S. Sneddon, J.S. Leon, I.M. Dick, et al (Gene, 2015).

The study

• Authors: S. Sneddon, J.S. Leon, I.M. Dick, G. Cadby, N. Olsen, F. Brims, R.J. Allcock, E.K. Moses, P.E. Melton, N. de Klerk, A.W. Musk, B.W. Robinson, J. Creaney
• Journal: Gene
• Published: 2015;563(1):103-5
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed individuals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected individuals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM.

Copyright © 2015. Published by Elsevier B.V.

In plain English

In this short communication from Western Australia, the authors examined germline (inherited) DNA from 115 unrelated, mostly European-Australian patients with malignant mesothelioma, randomly selected from an earlier cohort. They sequenced a 3,584-base-pair region of BAP1 covering all its exons and untranslated end regions; other researchers had earlier reported inherited BAP1 mutations in some mesothelioma patients. Twelve were women, and most were known to have been exposed to asbestos. Fiber types and tumour sites were not reported. No germline BAP1 mutations of any known functional significance were found. The authors reported eight known SNPs (a kind of DNA variant), though their table of eight includes a one-letter insertion and two entries without a reference SNP number. The three variants inside exons were synonymous and of no known functional significance. The insertion, seen in 7 samples, was of unknown significance. For the 115 cases, the upper 95% confidence limit for such mutations was 2.6%. The authors concluded that germline BAP1 mutations are not a major predisposing factor to asbestos-induced mesothelioma in Australian population-based studies. They noted that other, as yet unknown genetic factors may be present.

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: Short communication; laboratory genetic study (targeted sequencing of a 3,584-base-pair region of the BAP1 gene, covering all exons and the 3′ and 5′ untranslated regions, in germline DNA from a series of mesothelioma patients)
• Who was studied: 115 unrelated, predominantly European-Australian malignant mesothelioma patients (12 female), randomly selected from a previously described cohort; Western Australian research centre; dates of diagnosis not given. Histology: 60 epithelial, 14 biphasic, 6 sarcomatoid, 35 unspecified or diagnosed on immunocytological grounds; mean age at diagnosis 68 years (range 42 to 94).
• Exposure: The study looked for inherited mutations in the BAP1 gene, not at asbestos dose. The article reports that most patients were known to have been exposed to asbestos. The printed figure reads 'N90%', most likely 'more than 90%'. Fiber types and jobs are not reported.
• Main results:
  • No germline BAP1 mutations of any known functional significance were found in the 115 mesothelioma cases.
  • The text reports 8 known SNPs in the BAP1 region, with minor allele frequencies from 0.1 to 3.4%. Its Table 1 of eight variants includes a single-base insertion, and two entries have no reference SNP number ('ND').
  • The three SNPs in exons were synonymous and of no known functional significance.
  • A single base insertion in an intronic region between exons 1 and 2 was found in 7 samples and was of unknown significance.
  • The frequency of SNPs within BAP1 in this group (0.089%) matched the expected rate (0.1%).
  • If 7.7% of patients carried such mutations, as earlier reported, the probability of finding none in 115 cases was p = 0.0001. The upper 95% confidence limit for the mutation rate was 2.6% for these 115 cases, or 1.0% with all 3 studies on sporadic mesothelioma combined.
  • No indication of familial BAP1 mutations was found in eight families in which first-degree relatives also developed mesothelioma (data not shown).
  • Median survival for the group was 15 months (95% CI 11 to 19).
• The authors' conclusion: The authors concluded that germline BAP1 mutations are not a major predisposing factor to asbestos-induced mesothelioma in Australian population-based studies.
• Limitations the authors state:
  • The authors noted that other, as yet unknown genetic susceptibility factors may be present.
  • The authors stated that whether genetic factors play a role in mesothelioma remains unclear.

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: Germline Mutation, BAP1, Malignant Mesothelioma, Mesothelioma, Somatic Mutation, BAP1 Tumor Predisposition Syndrome.

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• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)
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