Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma

Our plain-English summary of Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma, by V. Panou, M. Gadiraju, A. Wolin, et al (Journal of Clinical Oncology, 2018).

The study

• Authors: V. Panou, M. Gadiraju, A. Wolin, C.M. Weipert, E. Skarda, A.N. Husain, J.D. Patel, B. Rose, S.R. Zhang, M. Weatherly, V. Nelakuditi, A. Knight Johnson, M. Helgeson, D. Fischer, A. Desai, N. Sulai, L. Ritterhouse, O.D. Røe, K.K. Turaga, D. Huo, J. Segal, S. Kadri, Z. Li, H.L. Kindler, J.E. Churpek
• Journal: Journal of Clinical Oncology
• Published: 2018;36(28):2863-2871
• Cited by: 192 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM).

Methods: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM.

Results: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54).

Conclusion: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.

In plain English

This study tested 198 mesothelioma patients for inherited (germline) mutations in 85 cancer susceptibility genes. In all, 186 were enrolled prospectively at the University of Chicago Medicine mesothelioma clinic from April 2016 to August 2017, and 12 deceased patients came from an earlier tumor bank. Disease began in the pleura in 148, the peritoneum in 44, both sites in 3 and the tunica vaginalis in 3. Asbestos exposure was self-reported. Twenty-three patients (12%) carried a germline mutation, most often in BAP1. Mutations were found in 25% of peritoneal cases versus 7% of pleural cases. They were found in 26% with no known asbestos exposure versus 7% with definite exposure. Asbestos exposure (odds ratio 0.28; 95% CI 0.11 to 0.72) and older age were associated with lower odds of carrying a mutation. A second cancer was associated with higher odds (3.33; 1.22 to 9.07). Mutations in six genes, including BAP1, were more frequent than in a noncancer reference database. These comparisons were not adjusted for multiple testing. The authors concluded that the data support genetic testing for all mesothelioma patients. They noted referral bias, self-reported exposure and an assay that may underestimate mutations.

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 sequencing study of germline DNA from mesothelioma patients at one center, mostly prospectively consented, with comparison to a noncancer population database and tumor sequencing in a subset
• Who was studied: 198 unrelated patients with malignant mesothelioma. Of 250 eligible patients, 186 attended The University of Chicago Medicine mesothelioma clinic from April 2016 to August 2017 and consented prospectively. Another 12 were deceased patients from a historical tumor banking protocol with stored germline DNA. Site of origin: 148 pleura, 44 peritoneum, 3 pleura and peritoneum, 3 tunica vaginalis. Median age at diagnosis was 67 years, and 136 (69%) were male. Controls were the noncancer Exome Aggregation Consortium (ExAC) population (n = 53,105).
• Exposure: The main factor studied was germline mutations in 85 cancer susceptibility genes. Asbestos exposure was self-reported in a standardized interview as definite (104), probable (22), possible (35), none (35) or unknown (2). Exposure was classed as primary (occupational or environmental) or secondary (through family members). No fiber types were reported.
• Main results:
  • 23 (12%) of 198 patients carried a germline mutation. There were 24 mutations in 13 genes. BAP1 mutations were the most common, at 6 (25% of the mutations).
  • Mutations were found in 11 of 44 (25%) patients with peritoneal mesothelioma and in 11 of 148 (7%) with pleural mesothelioma.
  • Mutations were found in 9 of 35 (26%) patients with no known asbestos exposure and in 7 of 104 (7%) with definite exposure.
  • In univariable analysis, asbestos exposure was associated with decreased odds of carrying a germline mutation (OR 0.28; 95% CI 0.11 to 0.72).
  • In univariable analysis, older age was associated with decreased odds of carrying a germline mutation (OR 0.95; 95% CI 0.92 to 0.99; P = .01).
  • In univariable analysis, having a second cancer diagnosis was associated with increased odds of carrying a germline mutation (OR 3.33; 95% CI 1.22 to 9.07).
  • In multivariable analysis, age, asbestos exposure and a second cancer diagnosis all remained significant predictors.
  • The share of patients carrying a mutation rose with younger age at diagnosis, from 4% of those older than 75 years to 20% of those aged 55 or younger (test of trend P = .01).
  • Compared with the noncancer ExAC population, the odds of carrying a BAP1 mutation were higher in the mesothelioma patients (OR 1,658; 95% CI 199 to 76,224). Odds were also higher for BRCA2 (OR 5; 1.0 to 14.7), CDKN2A (OR 53; 6 to 249), TMEM127 (OR 88; 1.7 to 1,105), VHL (OR 51; 1.1 to 453) and WT1 (OR 20; 0.5 to 135; P = .049).
  • The patient-versus-control comparisons were not adjusted for multiple testing. The table marks only BAP1 and CDKN2A as remaining significant if a Bonferroni correction is used.
  • Of 54 tumors sequenced, 29 (52%) had at least one germline or acquired mutation in a homologous recombination DNA repair pathway gene.
  • Existing clinical genetic testing guidelines would have identified only 12 (52%) of the 23 germline mutation carriers.
• The authors' conclusion: The authors concluded that 12% of mesothelioma patients carry germline mutations in cancer susceptibility genes, especially those with peritoneal disease, a second cancer, young age at onset and minimal known asbestos exposure. They wrote that these data support clinical germline genetic testing for all patients with mesothelioma and provide a rationale for further study of the homologous recombination pathway.
• Limitations the authors state:
  • The germline test could not detect copy number variants, and variant interpretation was conservative, so the proportion of carriers may be underestimated.
  • The tumor gene panel did not include all homologous recombination pathway genes and may miss small copy number changes.
  • The study center is a tertiary referral center, so the study population is subject to referral bias.
  • Insufficient tumor tissue, and too few families with more than one mesothelioma case carrying non-BAP1 mutations, limited direct evidence of causation.
  • Family cancer history and prior asbestos exposure were self-reported, which may limit accuracy.

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, Malignant Mesothelioma, Next-Generation Sequencing (NGS), Tunica Vaginalis, BAP1, Odds Ratio, Asbestos Exposure, CDKN2A.

Related studies

• Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma — A. Bononi, K. Goto, et al. (2020)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma — S. Sneddon, J.S. Leon, et al. (2015)

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