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Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma

Mansfield, Aaron S. ; Peikert, Tobias ; Smadbeck, James B. ; 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 N. ; Bungum, Aaron O. ; Edell, Eric S. ; Dong, Haidong ; Cheville, John C. ; Aubry, Marie Christine ; Jen, Jin ; Vasmatzis, George

Journal of thoracic oncology, 2019-02, Vol.14 (2), p.276-287 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma
Autor: Mansfield, Aaron S. ; Peikert, Tobias ; Smadbeck, James B. ; 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 N. ; Bungum, Aaron O. ; Edell, Eric S. ; Dong, Haidong ; Cheville, John C. ; Aubry, Marie Christine ; Jen, Jin ; Vasmatzis, George
Assuntos: Antigens - genetics ; Chromoplexy ; Chromosomal rearrangements ; Chromothripsis ; Clonal Selection, Antigen-Mediated ; Computer Simulation ; DNA, Neoplasm - analysis ; Gene Dosage ; Gene Rearrangement ; Genomics ; HLA-A Antigens - genetics ; HLA-B Antigens - genetics ; Humans ; Lymphocytes, Tumor-Infiltrating ; Mesothelioma ; Mesothelioma - genetics ; Mesothelioma - pathology ; Neoantigens ; Peptides - genetics ; Peptides - immunology ; Pleural Neoplasms - genetics ; Pleural Neoplasms - pathology ; Receptors, Antigen, T-Cell - genetics ; Sequence Analysis, DNA - methods ; Sequence Analysis, RNA ; Survival Rate ; T-Lymphocytes - immunology ; Transcriptome - genetics
É parte de: Journal of thoracic oncology, 2019-02, Vol.14 (2), p.276-287
Notas: Authors’ Contributions
Bioinformatics analysis: G.V., E.G-R., J.B.S, F.K., S.J.M., C.S., S.H.J.
Sample collection: V.V.S., A.O.B., E.E., J.L.S.K., G.K.
Sample handling and processing: H.R., F.H., J.L.S.K., G.K., L.E., C.L.E., V.P.V.K.
Histologic analysis: V.V.S, H.R., J.C.C., M.C.A.
ELIspot: C.L.E., V.P.V.K.
Study design: A.S.M., T.P., J.J., G.V.
Review and approval of manuscript: all authors
Study conception: A.S.M., T.P., G.V.
Binding prediction: J.B.M.U.
Interpretation of results: A.S.M., T.P., H.D., S.N.M., G.V.
Drafting and revising manuscript: A.S.M, T.P., G.V.
Peptide synthesis and preparation: W.K.N., S.N.M., H.D., L.E., C.L.E., V.P.V.K.
Descrição: 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. 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. 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. 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma

United States: Elsevier Inc

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