Mesothelioma developing in carriers of inherited genetic mutations

Our plain-English summary of Mesothelioma developing in carriers of inherited genetic mutations, by Y. Yoshikawa, M. Emi, T. Nakano, et al (Translational Lung Cancer Research, 2020).

The study

• Authors: Y. Yoshikawa, M. Emi, T. Nakano, G. Gaudino
• Journal: Translational Lung Cancer Research
• Published: 2020;9(Suppl 1):S67-S76
• Type of article: Review
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is associated with the exposure to asbestos fibers. Recent discovery of the BAP1 cancer syndrome, a Mendelian disorder with high-penetrance autosomal dominant inheritance fostered the genotyping for nucleotide-level or larger structural alteration of germline DNA. Inherited heterozygous mutations of the BAP1 gene increase the susceptibility to carcinogenic fibers, leading to a concept of gene x environment interaction (GxE) as a pathogenetic mechanism of mesothelioma. Several studies on cohorts of unselected patients with mesothelioma or on familial/early-onset cohorts of mesothelioma cases converged on BAP1 as the more frequent germline mutated gene, followed by other genes involved in DNA repair and homologous recombination. Evidence has been emerging that patients with mesothelioma carrying germline mutations of BAP1 and of other genes, such as those involved in DNA repair and tumor suppressor genes, have better prognosis and higher chemosensitivity when compared with patients with germline wildtype Bap1. We report here a germline genomic analysis targeted 22 genes in a cohort of 101 Japanese patients irrespective of asbestos exposure, age at diagnosis, or personal or family history of cancer. By comparing the results with the Human Genetic Variation Database (HGVD) and the Genome Aggregation Database (gnomAD) we selected rare germline variants with a Combined Annotation Dependent Depletion (CADD) >20. We show here that 31 of 101 subjects were carrying 25 rare variants in 14 genes, neither reported in the HGVD nor in the gnomAD database for 14/25 variants. Besides pathogenic variants of BAP1, rare missense variants were found in genes encoding lysine-specific histone methyltransferase SETD2 and SETDB1 and genes encoding subunits of the mSWI/SNF chromatin remodeling complex. The complete scenario of the genetic background consisting of pathogenic germline variants required for the predisposition and GxE for pathogenesis of mesothelioma appears complex, and further large-scale studies are warranted.

2020 Translational Lung Cancer Research. All rights reserved.

In plain English

This article was a review of recent research on inherited (germline) gene changes in people with mesothelioma. It also reported new results from the authors' own genetic analysis. The authors read the reviewed studies as indicating that at least 10–12% of mesotheliomas depend on the patient's genetic background, with BAP1 the gene most often affected. In the new work, the authors sequenced 22 genes in 101 Japanese patients with mesothelioma (93 pleural, 8 peritoneal). Patients were enrolled regardless of asbestos exposure, age or cancer history, and 33 reported asbestos exposure. They kept variants that were absent or extremely rare in two genetic databases and scored as likely damaging. Of the 101 patients, 31 carried 25 such rare variants in 14 genes. Fourteen of the 25 variants were listed in neither database. Three patients had BAP1 changes, and 12 rare variants were in genes of the mSWI/SNF chromatin remodeling complex. For the new Japanese cohort, the article did not compare variant carriers with non-carriers by asbestos exposure. The authors concluded that these variants might not be a major factor in causing mesothelioma but could modify predisposition to it.

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: Review article, which also reports new targeted gene-sequencing results from a Japanese mesothelioma cohort
• Who was studied: Reviewed: published germline studies of mesothelioma patients. New data: 101 Japanese patients with mesothelioma (76 men, 25 women; 93 pleural, 8 peritoneal). They were enrolled regardless of asbestos exposure, age at diagnosis, or personal or family history of cancer. Dates and recruitment sites are not stated.
• Exposure: Inherited variants in 22 genes, including BAP1, CDKN2A, NF2, TP53, MLH1, SETD2, SETBP1 and mSWI/SNF subunit genes. Asbestos exposure was recorded only as reported: 33 patients (32.7%) said yes and 68 (67.3%) said no, where 'no' included patients not aware of any exposure. Fiber types and doses were not given.
• Main results:
  • In their review, the authors read the summarized published studies as indicating that at least 10–12% of mesotheliomas depend on patients' genetic background, mainly through BAP1 or homologous recombination repair genes. These are findings of earlier published studies, one coauthored by the first author, not of the new Japanese analysis.
  • In the authors' reading of the reviewed studies, BAP1 germline mutations were the most prevalent in all of them.
  • In the Japanese cohort, variants were kept only if they were absent or extremely rare in the HGVD and gnomAD databases and had a CADD damage score above 20.
  • 31 of the 101 Japanese patients carried rare variants in 14 genes, 25 variants in total. Three patients had 2 variants each.
  • 14 of the 25 variants found in the Japanese cohort were reported in neither the HGVD nor the gnomAD database.
  • In BAP1, two patients had loss-of-function mutations and one more patient had a possibly pathogenic missense mutation.
  • Splice-donor site mutations were found in CDKN2A and MLH1.
  • 12 rare missense variants were found in mSWI/SNF chromatin remodeling complex subunit genes among the Japanese patients.
  • Rare variants meeting the frequency and CADD criteria were also found in histone methyltransferase genes. The text names SETD2 and SETDB1, but the results table lists SETD2 and SETBP1.
• The authors' conclusion: The authors concluded that the germline variants found in the Japanese patients might not be a major factor in causing mesothelioma but could be a modifying factor in predisposition to it.
• Limitations the authors state:
  • The authors noted that accurately determining asbestos exposure is difficult.
  • The authors stated that the criteria for judging the clinical significance of germline variants need improvement, because many variants remain of uncertain significance.
  • The authors stated that further studies are needed to identify the full set of genes predisposing to mesothelioma.

Topics

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

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• A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations — S. Pastorino, Y. Yoshikawa, et al. (2018)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• The Influence of Genetic Variability on the Risk of Developing Malignant Mesothelioma — A. Franko, N. Kotnik, et al. (2018)
• How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers — K. Behrouzfar, K. Burton, et al. (2021)
• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)

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