Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma.

Panou, Vasiliki; Gadiraju, Meghana; Wolin, Arthur; Weipert, Caroline; Skarda, Emily; Husain, Aliya N.; Patel, Jyoti D.; Rose, Buerkley; Nelakuditi, Viswateja; Johnson, Alyssa E.; Helgeson, Maria; Fischer, David; Sulai, Nanna; Turaga, Kiran K.; Huo, Dezheng; Segal, Jeremy; Kadri, Sabah; Li, Zejuan; Kindler, Hedy L.; Churpek, Jane E.

doi:10.1200/jco.2018.36.15_suppl.8564

Cited by 9 publications

(8 citation statements)

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“…This study is amongst the first to elaborate on somatic BRCA mutations in malignant mesothelioma. The distribution of somatic BRCA mutations seen in this study mirrors the findings in germline BRCA with a higher frequency of BRCA2 mutations as compared to BRCA1 mutations [ 10 , 33 , 37 ]. The BRCA2 somatic alterations were limited to single nucleotide polymorphism in all cases similar to pre viously reported germline findings [ 10 ].…”

Section: Discussionsupporting

confidence: 79%

“…Panou et al, in their targeted capture and next generation sequencing study of 85 cancer susceptibility genes on germline DNA from 198 malignant mesothelioma patients, found BRCA1 germline mutations in 0.0051 proportion of mesothelioma patients included in their study compared to 0.002 estimate in the non-cancer population (p>0.05). In the same study, BRCA2 germline mutations were seen in 0.0152 proportion of mesothelioma patients as compared to the 0.003 estimate in non-cancer population (p=0.03) [ 10 ]. This translates to a prevalence of 8.1% for BRCA2 variants in malignant mesothelioma compared to 2.1% for BRCA1 in this US based study.…”

Section: Discussionmentioning

confidence: 99%

“…Airborne exposure to asbestos both in the form of short term, heavy occupational exposure, as well as chronic, low-level environmental exposure has been shown to portend an increased risk for developing malignant mesothelioma. However, not all exposed individuals develop the disease [ 9 ] and not all cases of malignant mesothelioma can be traced to asbestos exposure [ 10 ]. This is further highlighted by the lack of a corresponding decrease in the incidence of malignant mesothelioma, despite a substantial and successful global effort, including introduction of strict legislature and mining regulations, to limit asbestos exposure [ 11 ], [ 12 ], [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma

Krishnamurthy

Alghamdi

et al. 2023

Pleura and Peritoneum

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Objectives The aim of this study is to analyze the prevalence of somatic mutations in BRCA1 and BRCA2 in malignant mesothelioma and their putative impact on protein properties. Methods Eighteen cases of malignant mesothelioma were retrieved from the archives and for next generation sequencing analysis of BRCA1 and BRCA2 genes. Variants were analyzed using Ensembl VEP17, Polyphen 2.0 software, SIFT software, MutpredV2, and SWISS-MODEL homology-modeling pipeline server. Results BRCA2 variants were found in significantly higher percentage (22%) of cases (p=0.02). Five missense variants were identified. These were p.A2351P, p.T2250A, p.A895V, pG1771D, and p.R2034C. The SIFT scores of all except one were ≥ 0.03. The Polyphen scores of these four alterations were ≤0.899. In case of p.A2315, the SIFT score was 0.01, while the Polyphen 2 score was 0.921. MutPred2 scores were ≤0.180 for all. Loss of intrinsic disorder was predicted (Pr=0.32, p=0.07) for p.R2034C, while gain of intrinsic disorder was predicted for p.A2351P (Pr=0.36, p=0.01) and p.G1771D (Pr=0.34, p=0.02). Conclusions BRCA2 somatic variants were identified in 22% cases of malignant mesotheliomas in this study. The variants localize more frequently to the disordered regions of the protein and are predicted to affect the level of disorder.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma

Krishnamurthy

Alghamdi

et al. 2023

Pleura and Peritoneum

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“…Germline mutations that predispose to MPM were first identified in BAP1, but two recent studies also highlighted germline mutations in several other genes that are less common than in BAP1. They are mainly involved in cell-cycle, chromatin regulation and DNA repair (20)(21)(22)(23)(24). Up to 7% of MPM patients may have germline mutations, but experimental validations are needed to confirm that some of these genes are MPM susceptibility genes (like BAP1).…”

Section: Molecular Alterationsmentioning

confidence: 99%

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra-and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting in vitro model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or in silico biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.

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“…Although asbestos use is banned in many countries, asbestos-insulated buildings are present throughout the world and some countries are still manufacturing and using large quantities of asbestos (2). Germline mutations in BAP1 and in other cancer susceptibility genes such as PALB2, BRCA2, CHEK2 and MLH1 have been identified in about 10-15% of patients with MPM (3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

et al. 2021

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Background: There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. Methods:We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. Results:Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice.Conclusions: Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM.

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Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma.

Cited by 9 publications

References 5 publications

A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma

A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

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