Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma

Aaron Mansfield, Tobias D Peikert, James Smadbeck, Julia B.M. Udell, Enrique Garcia-Rivera, Laura Elsbernd, Courtney L. Erskine, Virginia P. Van Keulen, Farhad Kosari, Stephen J. Murphy, Hongzheng Ren, Vishnu V. Serla, Janet L. Schaefer Klein, Giannoula Karagouga, Faye R. Harris, Carlos Sosa, Sarah H. Johnson, Wendy Nevala, Svetomir Nenad Markovic, Aaron O. BungumEric Edell, Haidong M Dong, John Cheville, Marie Christine Aubry, Jin Jen, George Vasmatzis

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)276-287
Number of pages12
JournalJournal of Thoracic Oncology
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Mesothelioma
T-Lymphocytes
Carcinogens
Atlases
Asbestos
T-Cell Antigen Receptor
Tumor Burden
Major Histocompatibility Complex
Transcriptome
Computer Simulation
Immunotherapy
Patient Selection
Neoplasms
Clone Cells
Chromosomes
Genome
RNA
Mutation
Survival

Keywords

  • Chromoplexy
  • Chromosomal rearrangements
  • Chromothripsis
  • Mesothelioma
  • Neoantigens

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma. / Mansfield, Aaron; Peikert, Tobias D; Smadbeck, James; Udell, Julia B.M.; Garcia-Rivera, Enrique; Elsbernd, Laura; Erskine, Courtney L.; Van Keulen, Virginia P.; Kosari, Farhad; Murphy, Stephen J.; Ren, Hongzheng; Serla, Vishnu V.; Schaefer Klein, Janet L.; Karagouga, Giannoula; Harris, Faye R.; Sosa, Carlos; Johnson, Sarah H.; Nevala, Wendy; Markovic, Svetomir Nenad; Bungum, Aaron O.; Edell, Eric; Dong, Haidong M; Cheville, John; Aubry, Marie Christine; Jen, Jin; Vasmatzis, George.

In: Journal of Thoracic Oncology, Vol. 14, No. 2, 01.02.2019, p. 276-287.

Research output: Contribution to journalArticle

Mansfield, A, Peikert, TD, Smadbeck, J, Udell, JBM, Garcia-Rivera, E, Elsbernd, L, Erskine, CL, Van Keulen, VP, Kosari, F, Murphy, SJ, Ren, H, Serla, VV, Schaefer Klein, JL, Karagouga, G, Harris, FR, Sosa, C, Johnson, SH, Nevala, W, Markovic, SN, Bungum, AO, Edell, E, Dong, HM, Cheville, J, Aubry, MC, Jen, J & Vasmatzis, G 2019, 'Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma', Journal of Thoracic Oncology, vol. 14, no. 2, pp. 276-287. https://doi.org/10.1016/j.jtho.2018.10.001
Mansfield, Aaron ; Peikert, Tobias D ; Smadbeck, James ; Udell, Julia B.M. ; Garcia-Rivera, Enrique ; Elsbernd, Laura ; Erskine, Courtney L. ; Van Keulen, Virginia P. ; Kosari, Farhad ; Murphy, Stephen J. ; Ren, Hongzheng ; Serla, Vishnu V. ; Schaefer Klein, Janet L. ; Karagouga, Giannoula ; Harris, Faye R. ; Sosa, Carlos ; Johnson, Sarah H. ; Nevala, Wendy ; Markovic, Svetomir Nenad ; Bungum, Aaron O. ; Edell, Eric ; Dong, Haidong M ; Cheville, John ; Aubry, Marie Christine ; Jen, Jin ; Vasmatzis, George. / Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma. In: Journal of Thoracic Oncology. 2019 ; Vol. 14, No. 2. pp. 276-287.
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AU - Mansfield, Aaron

AU - Peikert, Tobias D

AU - Smadbeck, James

AU - Udell, Julia B.M.

AU - Garcia-Rivera, Enrique

AU - Elsbernd, Laura

AU - Erskine, Courtney L.

AU - Van Keulen, Virginia P.

AU - Kosari, Farhad

AU - Murphy, Stephen J.

AU - Ren, Hongzheng

AU - Serla, Vishnu V.

AU - Schaefer Klein, Janet L.

AU - Karagouga, Giannoula

AU - Harris, Faye R.

AU - Sosa, Carlos

AU - Johnson, Sarah H.

AU - Nevala, Wendy

AU - Markovic, Svetomir Nenad

AU - Bungum, Aaron O.

AU - Edell, Eric

AU - Dong, Haidong M

AU - Cheville, John

AU - Aubry, Marie Christine

AU - Jen, Jin

AU - Vasmatzis, George

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N2 - 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.

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KW - Mesothelioma

KW - Neoantigens

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