Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma

Our plain-English summary of Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma, by M. Betti, E. Casalone, D. Ferrante, et al (Cancer Letters, 2017).

The study

• Authors: M. Betti, E. Casalone, D. Ferrante, A. Aspesi, G. Morleo, A. Biasi, M. Sculco, G. Mancuso, S. Guarrera, L. Righi, F. Grosso, R. Libener, M. Pavesi, N. Mariani, C. Casadio, R. Boldorini, D. Mirabelli, B. Pasini, C. Magnani, G. Matullo, I. Dianzani
• Journal: Cancer Letters
• Published: 2017;405:38-45
• Cited by: 79 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos exposure than did all the other patients (p = 0.0015). This suggests that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis. This study shows that germline variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment.

Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

In plain English

This genetic study looked for inherited gene changes in 93 Italian patients with malignant pleural mesothelioma living in Piedmont, northern Italy. Sixteen had a family history of mesothelioma. For 90 of them, lifetime asbestos exposure had been estimated from interviews about exposure at work, at home and in the general environment. The authors sequenced 94 cancer-related genes from blood samples and compared the results with 96 Italian controls matched for birth date, sex and town. Nine patients (9.7%) carried truncating variants that the authors classed as pathogenic, in ten DNA-repair genes including BRCA1, BRCA2, PALB2 and ATM. No such variants were found in the controls. The average estimated exposure was 3.8 in patients with these variants and 24.9 in patients without them, a statistically significant difference. Age at diagnosis, survival, tumor type and exposure category did not differ significantly between the groups. The authors suggested that in these patients even low asbestos exposure might have been enough to cause the tumor. They noted that their method may have missed some carriers, because it could not detect large rearrangements or changes in genes outside the panel.

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 study: targeted next-generation sequencing of 94 cancer-predisposition genes in mesothelioma patients, compared with a control group
• Who was studied: 93 Italian patients with malignant pleural mesothelioma, all living in Piedmont (northern Italy). 77 were randomly selected from earlier case-control studies and classed as sporadic, and 16 had a family history of mesothelioma. They were compared with 96 Italian controls (71 healthy, 25 hospitalized for non-neoplastic, non-respiratory conditions) matched for date of birth (within 5 years), gender and town (Casale Monferrato or Turin).
• Exposure: Asbestos exposure (fiber type not specified), classified as occupational (57% of patients), para-occupational (18%), environmental (20%) or household (1%). No exposure information was available for 3 patients. Exposure was also quantified as a lifetime cumulative index: frequency times intensity times duration, summed over all exposure circumstances.
• Main results:
  • 9 of 93 patients (9.7%) carried pathogenic truncating variants, in ten genes: PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. One patient carried two (BRCA1 and FANCI).
  • No pathogenic truncating variants were found in the 96 controls. The 95% confidence interval for their prevalence in controls was 0 to 3.8%.
  • Mean quantitative asbestos exposure was 3.8 (SD 9.5) in patients with truncating variants and 24.9 (SD 145.3) in patients without them.
  • The difference in mean exposure between patients with and without truncating variants was statistically significant (p = 0.0015, after logarithmic transformation).
  • 14 patients (15%) carried rare missense or in-frame variants of unknown significance. Their exposure did not differ significantly from that of the 70 non-carrier patients (p = 0.38).
  • Patients with and without truncating variants did not differ significantly in histotype or category of asbestos exposure.
  • Patients with and without truncating variants did not differ significantly in age at diagnosis (mean 73.9 vs 67.4 years, p = 0.13) or in survival (p = 0.25).
• The authors' conclusion: The authors suggested that, although asbestos exposure is necessary for pleural mesothelioma, in patients carrying these DNA-repair gene variants even low asbestos exposure may be sufficient to cause the tumor. They hypothesized that these patients were less able to repair asbestos-induced DNA damage.
• Limitations the authors state:
  • The variant classification was conservative and excluded possibly pathogenic missense variants, so the number of carriers may be underestimated.
  • The sequencing method does not detect large rearrangements.
  • Genes outside the 94-gene panel were not examined.
  • The missense and in-frame variants remain of unknown significance until segregation and functional studies are done.

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, Pleural Mesothelioma, Asbestos Exposure, BAP1, Mesothelioma, Carcinogenesis.

Related studies

• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling — F. Novelli, Y. Yoshikawa, et al. (2024)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos — G. Brandi, M. Deserti, et al. (2020)
• A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma — K.A. Wadt, L.G. Aoude, et al. (2015)

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