The Genetic Landscape of Malignant Pleural Mesothelioma: Results from Massively Parallel Sequencing

Our plain-English summary of The Genetic Landscape of Malignant Pleural Mesothelioma: Results from Massively Parallel Sequencing, by M. Hylebos, G. Van Camp, J.P. van Meerbeeck, et al (Journal of Thoracic Oncology, 2016).

The study

• Authors: M. Hylebos, G. Van Camp, J.P. van Meerbeeck, K. Op de Beeck
• Journal: Journal of Thoracic Oncology
• Published: 2016;11(10):1615-26
• Type of article: Review
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare yet aggressive tumor that is causally associated with-mostly professional-asbestos exposure. Given the long latency between exposure and disease, and because asbestos is still being used, MPM will remain a global health issue for decades to come. Notwithstanding the increasing incidence of MPM and the fact that patients with MPM face a poor prognosis, currently available treatment options are limited. To enable the development of novel targeted therapies, identification of the genetic alterations underlying MPM will be crucial. The first studies reporting on the genomic background of MPM identified recurrent somatic mutations in a number of tumor suppressor genes (i.e., cyclin-dependent kinase inhibitor 2A gene [CDKN2A], neurofibromin 2 (merlin) gene [NF2], and BRCA1 associated protein 1 gene [BAP1]). More recently, massively parallel sequencing strategies have been used and have provided a more genome-wide view on the genetic landscape of MPM. This review summarizes their results, describing alterations that cluster mainly in four pathways: the tumor protein p53/DNA repair, cell cycle, mitogen-activated protein kinase, and phosphoinisitide 3-kinase (PI3K)/AKT pathways. As these pathways are important during tumor development, they provide interesting candidates for targeting with novel drugs.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This article was a review, not a new study. The authors searched PubMed, Medline, Web of Science and abstracts from three cancer conferences for studies that used massively parallel (next-generation) sequencing on malignant pleural mesothelioma tissue. They summarized seven such studies. In one, Bueno et al. sequenced the whole genome of one tumor and a matched normal lung sample. In another, Guo et al. sequenced the protein-coding DNA of 22 tumors and found 517 somatic mutations in 490 genes, most often in BAP1 and next in NF2. The largest reviewed study, by Lo Iacono et al., examined 123 tumor samples. The authors wrote that, so far, no links had been found between genetic findings and age, sex or asbestos exposure. They concluded that the reported mutations clustered mainly in four pathways (TP53/DNA repair, cell cycle, MAPK and PI3K/AKT) and that no single common driver gene stood out. In their view, several mutations likely need to accumulate. They noted that the reviewed studies had small samples, sometimes lacked matched normal tissue, sometimes used tissue from treated patients, and in some cases used outdated sequencing platforms.

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 (concise state-of-the-art review) of published studies and congress abstracts using massively parallel sequencing in malignant pleural mesothelioma
• Who was studied: Studies that applied next-generation sequencing to malignant pleural mesothelioma tissue, found in PubMed, Medline, Web of Science and abstracts from ASCO, International Mesothelioma Interest Group and World Conference on Lung Cancer meetings. Seven studies (2008 to 2016) are listed in Table 1. Sample sizes ranged from one tumor (Bueno et al.; Kang et al. exome) to 123 tumor samples (Lo Iacono et al.).
• Exposure: No specific asbestos exposure, fiber type or dose was studied; the review concerns genetic changes in mesothelioma tissue. The authors describe MPM as causally associated with mostly professional asbestos exposure. One reviewed study (Mäki-Nevala et al.) further validated only variants found in its 18 asbestos-exposed individuals.
• Main results:
  • Bueno et al. sequenced the whole genome of only one primary MPM and a matched normal lung sample; 30 tumor-specific rearrangements disrupted 17 genes.
  • Guo et al. sequenced the exomes of 22 MPMs with paired blood samples and detected 517 somatic mutations in 490 genes. BAP1 was mutated most often and NF2 second most often. A focal 9p21 deletion including CDKN2A and CDKN2B was found in 10 of the MPMs.
  • Sugarbaker et al. sequenced the transcriptomes of four MPMs. Seven tumor-specific variants were checked in 49 MPMs, and three of them were observed in at least one additional tumor.
  • Kang et al. examined SETDB1 in tissue from 68 additional patients and found four point mutations and three deletions; 10 matched normal pleura samples showed no SETDB1 variants.
  • In Lo Iacono et al. (123 samples), BAP1 staining was considered positive in 52% of MPM samples and NF2 staining in 92%.
  • Taking the studies together, the authors found no single common driver gene and considered it more likely that several mutations accumulate for MPM to develop.
  • The authors stated that, so far, no correlations had been found between genotype and age, sex, or asbestos exposure.
• The authors' conclusion: The authors concluded that the studies reviewed detected mutations in four main pathways (TP53/DNA repair, cell cycle, MAPK and PI3K/AKT). They hypothesized that only a minority of somatic variations in MPM have been identified, and that larger studies on newer sequencing platforms are needed.
• Limitations the authors state:
  • Sample sizes in the reviewed studies were rather limited.
  • Detection of true tumor-specific mutations was hampered because matched normal material was missing in some cases and tissue from treated patients was used.
  • Some sequencing platforms used (Illumina Genome Analyzer 2 and Roche/454 GS20) are outdated and prone to some errors.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Latency, Prognosis, Somatic Mutation, Tumor Suppressor Gene, CDKN2A, Merlin.

Related studies

• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)
• Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma — D. Jean, E. Thomas, et al. (2011)
• Tumor-specific genetic variants can be detected in circulating cell-free DNA of malignant pleural mesothelioma patients — M. Hylebos, K. Op de Beeck, et al. (2018)
• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)
• Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing — S. Mäki-Nevala, V.K. Sarhadi, et al. (2016)

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