Mesothelioma in the age of "Omics": Before and after The Cancer Genome Atlas

Our plain-English summary of Mesothelioma in the age of "Omics": Before and after The Cancer Genome Atlas, by D.T. Severson, A. De Rienzo, R. Bueno (The Journal of Thoracic and Cardiovascular Surgery, 2020).

The study

• Authors: D.T. Severson, A. De Rienzo, R. Bueno
• Journal: The Journal of Thoracic and Cardiovascular Surgery
• Published: 2020;160(4):1078-1083.e2
• Type of article: Editorial, Comment
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a highly fatal cancer of the pleura that has been defeating standard and investigational therapies since its first description. The efficacies of chemotherapy, radiotherapy, and surgical therapy are limited, and we have been writing for decades that improved therapies are needed. MPM is born of inflammation, and approximately 80% of cases are associated with the smoldering tissue inflammatory responses against the carcinogenic fibers of asbestos. Emerging data on the use of programmed cell death protein 1 immune checkpoint inhibitors were initially exciting, but response is less than 20% and these agents are finding their place on the list of approaches with narrow efficacy. Molecular targeted therapies have revolutionized the treatment of other cancers, commonly result in striking antitumor responses, and directly embody precision medicine. For an example, we prescribe drugs for some lung adenocarcinomas that target the secondary mutations that develop as a resistance mechanism to their initial targeted therapy. The discovery of molecular therapeutics for any tumor begins with identification of a target through investigation of the genomic, epigenomic, and transcriptomic drivers of its carcinogenesis. Such an advance could revolutionize the treatment of mesothelioma. A comprehensive dissection of MPM’s molecular structure was recently published by 2 groups, the first from the Brigham and Women’s Hospital and then from The Cancer Genome Atlas. In the Invited Expert Opinion article that follows, a practical account of the molecular underpinnings of MPM is eloquently presented by the Brigham group and will inspire the discovery and translation of novel molecular targets by mesothelioma investigators and practitioners.

In plain English

This article was an invited expert opinion, a review by a research group at Brigham and Women's Hospital in Boston, about genetic and molecular studies of malignant pleural mesothelioma. The authors described the disease as caused by prior asbestos exposure, but the article did not study asbestos exposure itself. They reviewed earlier work, including their own 2016 study of 211 tumor samples. Their main focus was a 2018 study of 74 tumors by The Cancer Genome Atlas (TCGA). As the review reports it, that study found loss of gene regions containing CDKN2A in 41 (56%) and NF2 in 55 (74%) of the 74 tumors. It also sorted tumors into 4 groups linked to tissue type. The authors added a new analysis of previously published data from three tumor series. They found that a two-gene score (the CLDN15/VIM, or C/V, score) was significantly correlated with three other published measures of epithelioid-mesenchymal transition (EMT). The authors concluded that the C/V score may be an alternative way to measure this feature using only 2 genes.

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: Invited expert opinion (narrative review) of genomic and transcriptomic studies of malignant pleural mesothelioma, with a small new correlation analysis of previously published tumor gene-expression data
• Who was studied: No new patients were studied. The authors reanalyzed published RNA-sequencing profiles from the TCGA study (74 tumors) and from their own cohort (211 tumor samples), plus microarray profiles from a series published by Blum and colleagues.
• Exposure: Not studied. The authors state as background that malignant pleural mesothelioma is caused by prior asbestos exposure. No fiber types are named.
• Main results:
  • In the authors' own new analysis, the C/V score was significantly correlated with all 3 EMT metrics (E-score, S-score and the EMTCreighton score) across the three tumor series.
  • In the figure, the correlation between the C/V score and the EMTCreighton score had an R2 of 0.662 in the authors' (Bueno) RNA-seq series, 0.572 in the Blum microarray series and 0.571 in the TCGA RNA-seq series. Each was shown with P less than .001.
  • As reported from the TCGA study (Hmeljak and colleagues), loss of regions containing CDKN2A was found in 41 (56%) of 74 tumors, and loss of regions containing NF2 in 55 (74%) of 74 tumors.
  • As reported from the TCGA study, a subgroup with 'genomic near haploidization' made up 5 (3%) of 154 tumors examined (3 TCGA cases plus 2 Japanese International Cancer Genome Consortium cases).
  • As reported from the TCGA study, two clustering methods each identified 4 distinct groups of tumors. These groups were significantly associated with histology: cluster 1 was enriched for epithelioid tumors and cluster 4 for sarcomatoid tumors.
  • The authors' earlier 2016 study, which they summarize, published RNA-sequencing profiles of 211 tumor samples and identified 4 molecular clusters roughly associated with the spectrum from epithelioid to sarcomatoid histology.
• The authors' conclusion: The authors concluded that the C/V score may be an alternative way to measure the EMT component of each tumor using only 2 genes. They also concluded that sequencing studies, including the 2018 TCGA study, have improved molecular and genetic understanding of the disease.
• Limitations the authors state:
  • The authors state that little is understood about how tumors vary within a single patient, and that studies sampling multiple sites within a tumor or using single-cell sequencing are needed.

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: Mesothelioma, Pleural Mesothelioma, Pleura, Chemotherapy, Inflammation, Carcinogenic, checkpoint inhibitors, Lung Adenocarcinoma.

Related studies

• Conventional and novel "omics"-based approaches to the study of carbon nanotubes pulmonary toxicity — C. Ventura, A. Sousa-Uva, et al. (2018)
• Commentary: Tasting individual ingredients of meso soup: Can 'omics bring out the flavor? — H.I. Pass (2020)
• Variation in number of general practitioner consultations before hospital referral for cancer: findings from the 2010 National Cancer Patient Experience Survey in England — G. Lyratzopoulos, R.D. Neal, et al. (2012)
• Value of laparoscopy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis — L.H. Iversen, P.C. Rasmussen, et al. (2013)
• Variation in the peritoneal cancer index scores between surgeons and according to when they are determined (before or after cytoreductive surgery) — D. Elias, A. Souadka, et al. (2012)
• T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma — H. Vroman, G. Balzaretti, et al. (2020)

Browse more research in The Journal of Thoracic and Cardiovascular Surgery, or return to medical research.