Novel Germline Mutations in DNA Damage Repair in Patients with Malignant Pleural Mesotheliomas

Our plain-English summary of Novel Germline Mutations in DNA Damage Repair in Patients with Malignant Pleural Mesotheliomas, by R. Guo, M. DuBoff, G. Jayakumaran, et al (Journal of Thoracic Oncology, 2020).

The study

• Authors: R. Guo, M. DuBoff, G. Jayakumaran, M.G. Kris, M. Ladanyi, M.E. Robson, D. Mandelker, M.G. Zauderer
• Journal: Journal of Thoracic Oncology
• Published: 2020;15(4):655-660
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Although next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g., DNA damage sensing and repair) involved in the etiology of many cancers and has directed new screening, prevention, and therapeutic approaches for patients and families, it has only recently been used in malignant pleural mesotheliomas (MPMs).

Methods: We analyzed the blood samples from patients with MPM using the NGS platform MSK-IMPACT to explore cancer-predisposing genes. The loss-of-function variants or pathogenic entries were identified, and clinicopathologic information was collected.

Results: Of 84 patients with MPM, 12% (10 of 84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than two first-degree family members with cancer than those without germline mutations (40% versus 12%; Fisher's exact test, p < 0.05). Novel, deleterious variants in mesotheliomas included MutS homolog 3 (1% [one of 84]; 95% confidence interval [CI]: 0%-7%), breast cancer gene 1-associated ring domain 1 (1% [one of 84]; 95% CI: 0%-7%), and RecQ-like helicase 4 (2% [two of 84]; 95% CI: 0%-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were breast cancer gene 1-associated protein 1 (4% [three of 84]; 95% CI: 1%-10%), breast cancer gene 2 (1% [one of 84]; 95% CI: 0%-7%), and MRE11 homolog, double strand break repair nuclease (1% [one of 84]; 95% CI: 0%-7%). One patient (1% [one of 84]; 95% CI: 0%-7%) had a likely pathogenic alteration in SHQ1, H/ACA ribonucleoprotein assembly factor that has not been associated with a heritable susceptibility to cancer.

Conclusions: Our study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of MPMs and suggests that targeting the members of these pathways for screening and treatment warrants further study.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This brief report from Memorial Sloan Kettering Cancer Center in New York looked for inherited (germline) gene changes in people with malignant pleural mesothelioma. The authors sequenced blood samples from patients treated there from March 2013 to October 2016. After exclusions, 84 patients were analyzed; 61% (51/84) reported definite or probable classic occupational asbestos exposure, and no fiber types were named. Ten of 84 (12%) carried harmful variants. Genes previously reported in mesothelioma were BAP1 (3/84, 4%; 95% CI 1-10%), BRCA2 (1/84, 1%; 0-7%) and MRE11A (1/84, 1%; 0-7%). Genes not reported in mesothelioma before were MSH3, BARD1 and, likely harmful, SHQ1 (each 1/84, 1%; 95% CI 0-7%) and RECQL4 (2/84, 2%; 0-9%). Nine of the ten involved DNA damage repair. Carriers more often had more than two first-degree relatives with cancer (40% vs 12%, p less than 0.05). Self-reported asbestos exposure was comparable between groups. The authors concluded that the findings support a role for DNA damage repair genes in mesothelioma and warrant further study. They noted the small sample size and that whether these mutations raise mesothelioma risk needs investigation.

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 analysis (germline sequencing of blood samples) of patients drawn from a prospectively enrolled mesothelioma cohort; brief report
• Who was studied: Patients with malignant pleural mesothelioma (all stages) who received care at Memorial Sloan Kettering Cancer Center, New York, March 2013 to October 2016. 88 had germline sequencing and 84 were analyzed after exclusions. They were mostly male (68%, 57/84) and non-Hispanic white (87%, 73/84), with a median age at diagnosis of 69 years.
• Exposure: Germline variants in cancer-predisposing genes, detected with the MSK-IMPACT sequencing panel (341 to 468 genes). Asbestos exposure was self-reported: 61% (51/84) reported definite or probable classic occupational exposure. No fiber types or doses were given.
• Main results:
  • Of the 84 patients analyzed, 12% (10/84) had pathogenic germline variants (founder mutations excluded).
  • Patients with germline mutations were more likely than those without to have more than 2 first-degree relatives with cancer: 40% vs 12%, p less than 0.05.
  • Mutations in genes previously reported in mesothelioma: BAP1 in 3/84 (4%; 95% CI 1-10%), BRCA2 in 1/84 (1%; 95% CI 0-7%) and MRE11A in 1/84 (1%; 95% CI 0-7%).
  • Variants not previously reported in mesothelioma: MSH3 in 1/84 (1%; 95% CI 0-7%), BARD1 in 1/84 (1%; 95% CI 0-7%) and RECQL4 in 2/84 (2%; 95% CI 0-9%).
  • One patient (1/84; 1%, 95% CI 0-7%) had a likely pathogenic SHQ1 mutation, a gene not previously linked to a cancer-predisposition syndrome or reported in mesothelioma.
  • Of the 10 pathogenic germline variants, 9 (90%) involve DNA damage repair.
  • Self-reported asbestos exposure, smoking history, age and race were comparable between patients with and without germline mutations. Definite or probable asbestos exposure was reported by 5 of 10 (50%) carriers and 46 of 74 (62%) non-carriers.
• The authors' conclusion: The authors concluded that their study lends further support to a role for aberrations in DNA damage repair genes in the development of malignant pleural mesothelioma. They said that targeting these pathways for screening and treatment warrants further study.
• Limitations the authors state:
  • The small sample size makes it difficult to know whether the mutation frequencies found represent those in the general population.
  • The sequencing method (NGS) can be less reliable for large insertions/deletions and copy number changes, so germline mutations may be underrepresented.
  • Further investigation is needed to determine whether these germline mutations increase the risk of mesothelioma.
  • The RECQL4 and MSH3 mutations found were heterozygous, whereas these genes have only been reported in cancer predisposition syndromes in biallelic states. Their contribution to mesothelioma requires further investigation.
  • MSH3 was the only identified gene that was not tested on all versions of the sequencing panel.
  • Founder mutations (2 in BRCA2, 2 in APC) were excluded because their background rate in this cohort is unknown.

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, Next-Generation Sequencing (NGS), Etiology, Mesothelioma, confidence interval.

Related studies

• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• 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 Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design — F. Passiglia, P. Bironzo, et al. (2021)
• Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling — F. Novelli, Y. Yoshikawa, et al. (2024)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)

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