Chromosomal rearrangements and their neoantigenic potential in mesothelioma

Our plain-English summary of Chromosomal rearrangements and their neoantigenic potential in mesothelioma, by A.S. Mansfield, T. Peikert, G. Vasmatzis (Translational Lung Cancer Research, 2020).

The study

• Authors: A.S. Mansfield, T. Peikert, G. Vasmatzis
• Journal: Translational Lung Cancer Research
• Published: 2020;9(Suppl 1):S92-S99
• Type of article: Review
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Chromosomal rearrangements are a defining molecular feature of mesothelioma that are not readily detected by standard DNA sequencing approaches but could be detected by whole genome sequencing methods such as mate-pair sequencing. These chromosomal rearrangements result in novel, unique gene junctions that can be expressed and potentially result in the presentation of several neoantigens. These predicted neoantigens can be presented by tumors on major histocompatibility complex (MHC) proteins and are correlated with clonal expansion of tumor infiltrating T cells. T cells responsive to these neoantigens have been identified in the circulation of a patient. The predictive values of next generation sequencing-based tumor mutation burden measurements may be significantly enhanced by the addition of techniques such as mate-pair sequencing that can detect chromosomal rearrangements. Furthermore, rearrangement associated neo-antigens may also represent valuable targets for future anti-tumor vaccine strategies. Finally, chromosomal rearrangements are now recognized as a mutation signature in cancer and these events are likely to be important in the oncogenesis and immune recognition of not only in mesothelioma but multiple malignancies including non-small cell lung cancer.

2020 Translational Lung Cancer Research. All rights reserved.

In plain English

This was a review article in which the authors described their own earlier research on chromosomal rearrangements (large-scale breaking and rejoining of chromosomes) in malignant pleural mesothelioma. The article did not study asbestos exposure. In the earlier work, a whole-genome method called mate-pair sequencing found 1,535 rearrangements in 22 tumor specimens (median 41, range 3 to 298). A pattern called chromothripsis was seen in 10 of 22 specimens and chromoplexy in 9 of 22. In 87 mesothelioma cases from The Cancer Genome Atlas, 69% had copy-number changes consistent with chromothripsis. The 23 patients with 3 or more chromothripsis-like patterns had significantly worse survival than the 64 with 0 to 2 (hazard ratio 2.002, P=0.006). In one tumor, 75 rearrangement-derived peptides were predicted to bind that patient's HLA immune molecules, and three tested peptides bound well in a laboratory assay. More predicted neoantigens were correlated with expansion of tumor-infiltrating T cells. In one further patient, T cells in the blood responded to predicted neoantigens. The authors concluded these findings may have implications for immunotherapy.

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 article summarizing the authors' own prior study of chromosomal rearrangements in mesothelioma
• Who was studied: 22 malignant pleural mesothelioma specimens analyzed by mate-pair sequencing and RNA sequencing; the mesothelioma cohort (n=87) of The Cancer Genome Atlas; and one additional patient who had surgery for mesothelioma at the authors' institution
• Exposure: No asbestos or other exposure was studied. The work concerned chromosomal rearrangements (chromothripsis and chromoplexy) in tumor DNA and the immune responses they may trigger.
• Main results:
  • In 22 malignant pleural mesothelioma specimens, 1,535 chromosomal rearrangements were found (median 41, range 3 to 298 per specimen)
  • Among the 22 specimens, chromothripsis was present in 10 (45%), chromoplexy in 9 (41%), and both in 7 (32%)
  • 69% of mesothelioma specimens in The Cancer Genome Atlas had copy number changes consistent with chromothripsis
  • In The Cancer Genome Atlas mesothelioma cohort, survival was significantly worse for the 23 patients with 3 or more chromothripsis-like patterns than for the 64 with 0 to 2 (HR 2.002, P=0.006)
  • In one case (ME018), 75 of 1,146 peptides from expressed rearrangements were predicted to bind the patient's specific HLA molecules
  • Three selected candidate peptides from that case bound HLA-A*24:02 very well in a competitive binding assay
  • A positive correlation was detected between T cell productive clonality and chromosomal rearrangements, rearrangements involving genes, and predicted neoantigens (no correlation values given in this article)
  • In one additional patient, T cells responsive to predicted rearrangement-related neoantigens were found in the blood
• The authors' conclusion: The authors concluded that these findings may have implications for immunotherapy, and that adding mate-pair sequencing and identifying rearrangement-associated neoantigens may significantly enhance the predictive value of tumor mutation burden measurements

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Carcinogenesis, Non-Small Cell Lung Cancer.

Related studies

• Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma — A.S. Mansfield, T. Peikert, et al. (2019)
• Individualized Cell-Free DNA Monitoring With Chromosomal Junctions for Mesothelioma — K. Parikh, F.R. Harris, et al. (2024)
• The diversity of soft tissue tumours with EWSR1 gene rearrangements: a review — C. Fisher (2014)
• Identification of ALK Rearrangements in Malignant Peritoneal Mesothelioma — Y.P. Hung, F. Dong, et al. (2018)
• NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer — J.L. Leal, G. Peters, et al. (2020)
• Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement — G. Bronte, A. Delmonte, et al. (2020)

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