Molecular Characterization of Malignant Mesothelioma: Time for New Targets?

Our plain-English summary of Molecular Characterization of Malignant Mesothelioma: Time for New Targets?, by C. Aggarwal, S.M. Albelda (Cancer Discovery, 2018).

The study

• Authors: C. Aggarwal, S.M. Albelda
• Journal: Cancer Discovery
• Published: 2018;8(12):1508-1510
• Type of article: Comment
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive lethal malignancy for which very few therapeutic options exist. In this issue of Cancer Discovery, Hmeljak and colleagues report on a comprehensive integrative analysis of histology-independent genomic characteristics of MPM. They confirm previous observations that inactivation of tumor suppressor genes is the predominant oncogenic mechanism. This study provides a scientific rationale for potentially novel therapeutic options, including immune-checkpoint targeting VISTA and small-molecule inhibitors targeting the epigenome, DNA-repair pathways, and aurora kinase.See related article by Hmeljak et al., p. 1548.

©2018 American Association for Cancer Research.

In plain English

This article is a short commentary, not an original study. The authors discussed a separate study by Hmeljak and colleagues that analyzed the genes and molecular features of tumors from 74 patients with malignant pleural mesothelioma. As the authors described it, that study found that all but one sample had a low tumor mutational burden (fewer than 2 nonsynonymous mutations per megabase). It found BAP1 alterations in 57% of all samples and deep (homozygous) deletions of the CDKN2A gene in about 49% of patients. It reported strong expression of VISTA, an immune checkpoint protein, in mesothelioma cells. It also found that mutations were not related to smoking history or asbestos exposure. It identified four molecular subgroups with different outlooks. Homozygous CDKN2A deletions were seen in 11% of the best-prognosis group and 66% of the poorest-prognosis group. The authors suggested that the methods used may underestimate the neoantigen load. They also noted that the study could not clearly separate genetic features by gender or smoking history. The authors concluded that the work offers new pathways to explore, including AURKA inhibitors, dual checkpoint immunotherapy and VISTA inhibition.

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: Commentary (an 'In the Spotlight' piece) on another study, Hmeljak et al., published in the same journal issue; not original research
• Who was studied: No population studied directly. The commentary discusses the Hmeljak et al. study of 74 patients with malignant pleural mesothelioma.
• Exposure: No exposure studied directly. The commentary reports that, in the Hmeljak et al. study, mutations were not related to asbestos exposure or smoking history. No fiber types are named.
• Main results:
  • According to the commentary, in the Hmeljak et al. study all but one sample had low tumor mutational burden, with fewer than 2 nonsynonymous mutations per megabase
  • BAP1 alterations were found in 57% of all samples in the Hmeljak et al. study
  • Deep (homozygous) deletions in CDKN2A were found in about 49% of patients in the Hmeljak et al. study
  • The Hmeljak et al. study reported strong expression of VISTA in mesothelioma cells, the highest of any cancer type studied by TCGA
  • Mutations in the Hmeljak et al. study were not related to smoking history or asbestos exposure
  • The Hmeljak et al. study found very few targetable driver mutations in RTKs, the MAPK pathway or PI3/AKT signaling pathway genes
  • Four molecular subgroups with different prognoses were identified. The best-prognosis group (iCluster 1) had CDKN2A homozygous deletions in 11%, and the poorest-prognosis group (iCluster 4) had them in 66%.
  • According to the commentary, these prognostic molecular profiles were reproducible in samples from other cohorts
• The authors' conclusion: The authors concluded that the Hmeljak et al. study offers new pathways that can be explored, including AURKA inhibitors, dual checkpoint immunotherapy and VISTA inhibition
• Limitations the authors state:
  • The authors note that the Hmeljak et al. study cannot clearly differentiate genomic characteristics by gender or smoking history
  • The authors suggest, as one possible explanation for the low mutational burden, that the TCGA methods used may underestimate the neoantigen load in mesothelioma

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: Malignant Mesothelioma, Pleural Mesothelioma, Discovery, Histology, Tumor Suppressor Gene.

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• Molecular genetics and mechanisms of apoptosis in carcinomas of the lung and pleura: therapeutic targets — L.R. Motadi, N.L. Misso, et al. (2007)
• Molecular targets in malignant pleural mesothelioma treatment — G. Pasello, A. Favaretto (2009)
• miR-16: expanding the range of molecular targets in mesothelioma — D. Fennell (2017)
• Integrative Molecular Characterization of Malignant Pleural Mesothelioma — J. Hmeljak, F. Sanchez-Vega, et al. (2018)

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