Does Chromothripsis Make Mesothelioma an Immunogenic Cancer?

Our plain-English summary of Does Chromothripsis Make Mesothelioma an Immunogenic Cancer?, by M. Carbone, H. Yang, G. Gaudino (Journal of Thoracic Oncology, 2019).

The study

• Authors: M. Carbone, H. Yang, G. Gaudino
• Journal: Journal of Thoracic Oncology
• Published: 2019;14(2):157-159
• Type of article: Editorial, Comment
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Summary of the article

This editorial commented on a study by Mansfield et al., published in the same journal issue, that used mate-pair sequencing and RNA sequencing on tumors from 28 treatment-naive patients with malignant mesothelioma (MM). That study found chromosomal rearrangements, often with a pattern of chromothripsis or chromoplexy, across tumor subtypes. The editorial authors noted that earlier next-generation sequencing (NGS) studies had reported a low mutation burden in MM, averaging 23 mutations per biopsy specimen (range 2 to 51). This was hard to reconcile with older cytogenetic findings of many chromosomal abnormalities. They explained that NGS cannot reliably detect copy number changes, and that Mansfield et al. and an earlier study by Yoshikawa et al. found far more genetic alterations and identified chromothripsis as one cause. They described chromothripsis and stated that DNA damage in MM is enhanced by germline mutations and/or by exposure to asbestos and other carcinogenic fibers. They suggested that a higher-than-expected mutational burden might explain encouraging preliminary results with nivolumab. Mansfield et al. predicted neoantigens from the rearrangements and tested three synthetic peptides, linking predicted neoantigens to clonal expansion of tumor-infiltrating T cells. The editorial authors concluded that MM may be immunogenic. However, they cautioned that the advantage of immunotherapy over chemotherapy has not been demonstrated and that the existence of these neoantigens remains an unproven hypothesis.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This article is an editorial, not an original study. The authors commented on a study by Mansfield et al., published in the same journal issue, which examined chromosomes from 28 untreated patients with malignant mesothelioma. They reported that Mansfield et al. found rearrangements within and between chromosomes, frequently in patterns called chromothripsis or chromoplexy, regardless of tumor subtype. They contrasted this with earlier gene-sequencing studies that reported few mutations in mesothelioma, an average of 23 per biopsy. They also reported that, in Mansfield et al.'s laboratory tests, more predicted 'neoantigens' (small protein pieces, or peptides, that software predicted could be made from the rearrangements and recognized by the immune system) went along with expansion of tumor-infiltrating immune T cells. The authors concluded that mesothelioma may be an immunogenic tumor, one the immune system can recognize. They added that the advantage of immunotherapy over standard chemotherapy remains to be demonstrated. They also said the neoantigens had only been predicted by software, not directly shown to exist. They mentioned asbestos only in passing, as one factor that increases DNA damage.

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: Editorial commenting on another study (Mansfield et al.); no original data
• Who was studied: No population of its own; the editorial discusses Mansfield et al.'s study of 28 treatment-naive patients with malignant mesothelioma
• Exposure: No exposure studied; the authors mention asbestos and other carcinogenic fibers, along with inherited (germline) mutations, as increasing DNA damage in mesothelioma
• Main results:
  • As reported by the editorial: Mansfield et al. found interchromosomal or intrachromosomal rearrangements, with a frequent pattern of chromothripsis or chromoplexy, in the 28 patients regardless of tumor subtype
  • As reported by the editorial: earlier gene-sequencing (NGS) studies estimated an average of 23 mutations per mesothelioma biopsy specimen, with a range of 2 to 51
  • As reported by the editorial: in Mansfield et al., the increase in predicted neoantigens (peptides predicted to have neoantigenic potential) from chromosome rearrangements correlated with clonal expansion of tumor-infiltrating T cells
  • As reported by the editorial: in blood cells from one additional mesothelioma patient, Mansfield et al. found T cells that responded to that patient's predicted neoantigens
• The authors' conclusion: The authors concluded that, contrary to hypotheses based on NGS studies, malignant mesothelioma may be an immunogenic tumor. They added that the actual existence of the neoantigens remains a theoretical hypothesis.
• Limitations the authors state:
  • The authors noted that the mate-pair sequencing method cannot detect deletions smaller than about 3 kb
  • The authors noted that the advantage of immunotherapy over standard chemotherapy in mesothelioma remains to be demonstrated
  • The authors noted that neoantigen formation has only been predicted with software, and the evidence that the tumor cells actually express these peptides is indirect

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, Malignant Mesothelioma, Next-Generation Sequencing (NGS), Biopsy, Germline Mutation, Carcinogenic, Nivolumab (Opdivo), Immunotherapy.

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