Genomics and Functional Genomics of Malignant Pleural Mesothelioma

Our plain-English summary of Genomics and Functional Genomics of Malignant Pleural Mesothelioma, by E. Cakiroglu, S. Senturk (International Journal of Molecular Sciences, 2020).

The study

• Authors: E. Cakiroglu, S. Senturk
• Journal: International Journal of Molecular Sciences
• Published: 2020;21(17)
• Type of article: Review
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the mesothelial cells lining the pleural surface of the chest wall and lung. The etiology of MPM is strongly associated with prior exposure to asbestos fibers, and the median survival rate of the diagnosed patients is approximately one year. Despite the latest advancements in surgical techniques and systemic therapies, currently available treatment modalities of MPM fail to provide long-term survival. The increasing incidence of MPM highlights the need for finding effective treatments. Targeted therapies offer personalized treatments in many cancers. However, targeted therapy in MPM is not recommended by clinical guidelines mainly because of poor target definition. A better understanding of the molecular and cellular mechanisms and the predictors of poor clinical outcomes of MPM is required to identify novel targets and develop precise and effective treatments. Recent advances in the genomics and functional genomics fields have provided groundbreaking insights into the genomic and molecular profiles of MPM and enabled the functional characterization of the genetic alterations. This review provides a comprehensive overview of the relevant literature and highlights the potential of state-of-the-art genomics and functional genomics research to facilitate the development of novel diagnostics and therapeutic modalities in MPM.

In plain English

This article reviewed published research on the genetics of malignant pleural mesothelioma (MPM), a chest-lining cancer. It summarized studies on frequently altered genes such as BAP1, CDKN2A, NF2 and TP53, gene expression, chemical marks on DNA, experiments that switch genes off (including RNAi and CRISPR screens), drug screens, and cell, organoid and mouse models. The review named past asbestos exposure as the main cause of MPM but did not study it. The authors also ran two small analyses of public data. In 87 MPM patient samples from The Cancer Genome Atlas, NF2 was mutated in 23.3%, BAP1 in 20.9% and TP53 in 16.3%. In public screening data on five MPM cell lines, they found 10 genes all five cell lines depended on; all 10 had already appeared on a published list of common essential genes. Higher expression of three of these genes (RAN, RUVBL1 and SNRPD1) was significantly associated with lower overall survival. The authors concluded that clinical trials of targeted drugs in MPM had failed to give the expected results. In their view, genomics and functional genomics studies can help find new treatment targets.

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 of published literature on the genomics and functional genomics of malignant pleural mesothelioma, with two small proof-of-principle analyses of public databases (TCGA via cBioPortal; DepMap) by the authors
• Who was studied: Published studies of MPM tumors, cell lines and animal models. The authors' own analyses used 87 MPM patient samples in The Cancer Genome Atlas (TCGA) and five MPM cell lines in DepMap (H2052, H2452, H28, ACC-MESO-1, MPP89)
• Exposure: Not an exposure study. Asbestos is described as the primary cause of MPM (about 80% of cases, citing other sources). The review covers genetic, epigenetic and gene-expression changes in MPM.
• Main results:
  • In the authors' analysis of the 87 TCGA MPM samples, NF2 had a mutation frequency of 23.3% and a homozygous deletion frequency of 8.0%
  • In the same 87 TCGA MPM samples, BAP1 had a mutation frequency of 20.9% and a homozygous deletion frequency of 11.5%
  • In the same 87 TCGA MPM samples, TP53 had a mutation frequency of 16.3%
  • In the authors' DepMap analysis of five MPM cell lines, 10 genes (DDB1, EEF2, EIF3A, HSPE1, RAN, RPS15A, RUVBL1, SNRPD1, UBA1, VCP) were common essential genes in both the CRISPR and RNAi datasets and in all five cell lines
  • All 10 genes found in the DepMap analysis had previously been listed as common essential genes in another published study
  • In the 87 TCGA MPM cases, genetic changes in these 10 genes were infrequent: DDB1 was amplified in two cases and EEF2 in one, and EIF3A and RUVBL1 were deleted in two individual cases
  • In the authors' analysis using the GEPIA and UALCAN web portals, high expression levels of RAN, RUVBL1 and SNRPD1 were significantly associated with lower overall survival rates in MPM patients
• The authors' conclusion: The authors concluded that clinical trials of agents targeting key pathways in MPM failed to provide the expected results. They wrote that integrative, high-throughput genomics and functional genomics studies can help identify new targets and treatment strategies.
• Limitations the authors state:
  • The authors noted that commonly used cell lines and the xenograft models derived from them do not fully reproduce the genetic and phenotypic variety of human MPM
  • The authors noted that high-throughput RNAi and CRISPR screens are limited in MPM
  • The authors stated that the link between higher EIF3A expression and lower survival in their analysis was not statistically significant, and that larger MPM cohorts would be needed

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelial Cells, Etiology, Median Survival, Targeted Therapy.

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• Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma — D. Jean, E. Thomas, et al. (2011)
• Genomic characterization of malignant pleural mesothelioma and associated clinical outcomes — P. Markowitz, M. Patel, et al. (2020)
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