Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma

Our plain-English summary of Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma, by A.S. Mansfield, T. Peikert, J.B. Smadbeck, et al (Journal of Thoracic Oncology, 2019).

The study

• Authors: A.S. Mansfield, T. Peikert, J.B. Smadbeck, J.B.M. Udell, E. Garcia-Rivera, L. Elsbernd, C.L. Erskine, V.P. Van Keulen, F. Kosari, S.J. Murphy, H. Ren, V.V. Serla, J.L. Schaefer Klein, G. Karagouga, F.R. Harris, C. Sosa, S.H. Johnson, W. Nevala, S.N. Markovic, A.O. Bungum, E.S. Edell, H. Dong, J.C. Cheville, M.C. Aubry, J. Jen, G. Vasmatzis
• Journal: Journal of Thoracic Oncology
• Published: 2019;14(2):276-287
• Cited by: 108 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy.

Methods: We used mate-pair (n = 22), RNA (n = 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome.

Results: We observed that inter- or intrachromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific major histocompatibility complex molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient's circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival.

Conclusions: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study at Mayo Clinic examined the genetic material of tumors from people with malignant pleural mesothelioma. The article does not report a patient-level asbestos-exposure assessment. The authors studied 28 frozen tumor specimens taken before any systemic therapy. Twenty-two had enough DNA for mate-pair sequencing, a method that detects large chromosomal rearrangements. All 22 had rearrangements, from 3 to 298 each and 1535 in total. Complex patterns called chromothripsis appeared in 10 of the 22 specimens, and a pattern called chromoplexy in 9 of the 22. Computer predictions suggested these rearrangements could produce 179 new protein fragments that the immune system might recognize (potential neoantigens). Laboratory-made copies of three fragments predicted from one patient's tumor all bound one of that patient's immune (HLA) molecules in a binding test. In a second patient, a blood test suggested that T cells responsive to predicted fragments were present. In public data on 87 mesothelioma cases, those with 3 or more chromothripsis-like patterns had worse survival (hazard ratio 2.002). The authors concluded that chromosomal rearrangements may drive neoantigen expression in mesothelioma.

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: Laboratory genomic and immunologic study of stored tumor specimens (DNA mate-pair sequencing, RNA sequencing, T cell receptor sequencing, computer predictions, lab binding and blood assays), plus analysis of existing data from The Cancer Genome Atlas (TCGA)
• Who was studied: 28 frozen malignant pleural mesothelioma specimens from the Mayo Clinic Thoracic Specimen Registry or routine clinical care, obtained before any systemic therapy. 22 had enough DNA for mate-pair sequencing and all 28 had enough RNA for RNA sequencing. One additional patient's tumor and blood were collected prospectively. Copy number data from the TCGA mesothelioma cohort (87 cases) were also analyzed.
• Exposure: The article text does not report a patient-level asbestos-exposure assessment. Asbestos appears only as background in the introduction. Patient characteristics are in a supplementary table that is not included here. The study examined structural chromosomal rearrangements in tumor DNA and the protein fragments they were predicted to produce.
• Main results:
  • Among the 22 specimens there were 1535 chromosomal rearrangements (median 41, range 3 to 298 per specimen). 637 of these resulted in novel gene fusions.
  • RNA analysis predicted that the rearrangement junctions could produce 179 novel amino acid sequences that are potential neoantigens (median 5, range 0 to 51 per specimen). The predicted neoantigens were unique to each case.
  • Chromothripsis was present in 10 of 22 specimens (45%), chromoplexy in 9 of 22 (41%), and both in 7 of 22 (32%).
  • There were no significant differences in the frequency of rearrangements (p = 0.75), gene fusions (p = 0.57) or predicted neoantigens (p = 0.19) between epithelioid (n = 11) and biphasic or sarcomatoid (n = 10) subtypes.
  • Three candidate peptides predicted from case ME018's tumor were synthesized in the laboratory and tested in an MHC-peptide binding assay. All three bound HLA-A*24:02 very well or as well as a high-affinity positive control.
  • In the tumor specimens, more predicted neoantigens correlated with clonal expansion of tumor-infiltrating T cells (productive clonality, r2 = 0.31, p = 0.04).
  • In one additional, prospectively collected patient, 86 potential neoantigens were predicted. An IFN-gamma ELIspot assay using eight of these peptides suggested that T cells responsive to them were present in the patient's blood cells.
  • In the TCGA mesothelioma cohort (n = 87), 27, 22, 15 and 23 patients had 0, 1, 2, and 3 or more chromothripsis-like patterns (CTLPs). Those with 3 or more CTLPs had significantly worse prognosis than others (HR 2.002, p = 0.006). In a model including histology, both CTLPs (HR 2.2, p = 0.006) and histology (HR 1.9, p = 0.013) had a significant effect on survival.
• The authors' conclusion: The authors concluded that their data suggest neoantigen expression may be driven by structural chromosomal rearrangements in mesothelioma. They added that this may have implications for developing immunotherapies and selecting patients to receive them.
• Limitations the authors state:
  • There was not enough tissue and germline DNA to determine tumor mutation burden accurately or to assess its relationship to chromoanagenesis.
  • Evidence that the computer-predicted neoantigens exist is indirect, based on T cells recognizing them in the ELIspot assay. Direct evidence is ongoing work.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Discovery.

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• The diversity of soft tissue tumours with EWSR1 gene rearrangements: a review — C. Fisher (2014)
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• 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)
• Evaluation of RET Gene Rearrangement by Fluorescence In Situ Hybridization in Malignant Mesothelioma — S. Salvi, J.L. Ravetti, et al. (2018)

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