Exploring the Expression of the «Dark Matter» of the Genome in Mesothelioma for Potentially Predictive Biomarkers for Prognosis and Immunotherapy

Our plain-English summary of Exploring the Expression of the «Dark Matter» of the Genome in Mesothelioma for Potentially Predictive Biomarkers for Prognosis and Immunotherapy, by E. Felley-Bosco (Cancers, 2023).

The study

• Author: E. Felley-Bosco
• Journal: Cancers
• Published: 2023;15(11)
• Type of article: Review
• Read it: PubMed · Publisher · Free full text

Abstract

Recent high-throughput RNA sequencing technologies have confirmed that a large part of the non-coding genome is transcribed. The priority for further investigations is nevertheless generally given in cancer to coding sequences, due to the obvious interest of finding therapeutic targets. In addition, several RNA-sequencing pipelines eliminate repetitive sequences, which are difficult to analyze. In this review, we shall focus on endogenous retroviruses. These sequences are remnants of ancestral germline infections by exogenous retroviruses. These sequences represent 8% of human genome, meaning four-fold the fraction of the genome encoding for proteins. These sequences are generally mostly repressed in normal adult tissues, but pathological conditions lead to their de-repression. Specific mesothelioma-associated endogenous retrovirus expression and their association to clinical outcome is discussed.

In plain English

This article is a review by a single author about endogenous retroviruses (ERVs). ERVs are stretches of DNA left in the human genome by ancient virus infections, and the article says they cover 8% of the human genome. The review described how these sequences are normally kept silent and how they can become active again in disease, including mesothelioma. Much of the mesothelioma evidence it summarized came from the author's own earlier studies. In mice exposed to asbestos, ERV expression increased as mesothelioma developed. Tumor data from the TCGA and Bueno mesothelioma cohorts were compared with mesothelium grown from stem cells. ERVs made up on average 74% of the transposable elements that were more than two-fold upregulated and 48% of those more than two-fold downregulated. High expression of one ERV, ERVmap_1248, was associated with longer overall survival in three mesothelioma datasets. The author suggested that ERV expression could help select patients with epithelioid mesothelioma who might respond to immune checkpoint inhibitors, and called for prospective studies. The author noted that some RNA-sequencing methods miss repeat sequences.

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 (summary of published research, much of it the author's own earlier work, on endogenous retroviruses in mesothelioma)
• Who was studied: The review covered published research. For mesothelioma, it drew on the author's earlier analyses of tumor RNA-sequencing data from two mesothelioma cohorts (TCGA and Bueno's) and from FunGeST mesothelioma primary cell lines. These were compared with mesothelium derived from human embryonic stem cells as the non-tumor control. It also drew on an earlier study of asbestos-exposed mice.
• Exposure: This was not an exposure study. Asbestos is mentioned as a cause of mesothelioma and in the author's earlier mouse model; no fiber types or doses are given. The main subject is the expression of endogenous retroviruses in mesothelioma tumors.
• Main results:
  • In the author's earlier comparison of mesothelioma patient datasets with mesothelium, ERVs made up on average 74% of transposable elements upregulated more than two-fold and 48% of those downregulated more than two-fold.
  • In human mesothelioma tumors (author's earlier study), high expression of ERVmap_1248 was associated with longer overall survival in three mesothelioma datasets.
  • Tumor samples with the highest ERVmap_1248 expression also had the highest inflammatory signature score. This score predicts response to checkpoint inhibitors in the CheckMate743 trial.
  • In the author's earlier mouse study, 27 interferon-stimulated genes were more highly expressed in tumor samples than in samples from asbestos-exposed mice without tumors. Overexpression of six of these genes was associated with best overall survival in TCGA mesothelioma patients.
• The authors' conclusion: The author concluded that ERV expression could be useful for selecting patients with epithelioid mesothelioma who have the potential to respond to immune checkpoint inhibition. The author also said future studies should prospectively test ERVmap_1248 expression as a predictor of sensitivity to immunotherapy.
• Limitations the authors state:
  • The choice of RNA-sequencing method introduces a bias in the analysis of transposable element expression.
  • The only RNA-sequencing data for normal mesothelial cells came from a single-cell study. That study used a method that has been shown to miss several classes of repeat RNA, which is why stem-cell-derived mesothelium was used as the control.
  • Some forms of mesothelioma have lost type-I interferon genes, which matters for therapies that rely on type-I interferon signaling.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Biomarker, Prognosis, Immunotherapy.

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