Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma

March 26,2021

 
Oct. 10, 2018
 

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. 

Material and 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 intra-chromosomal 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 MHC 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. 

Discussion: 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.

 
Authors:
Virginia P. Van Keulen6Tobias Peikert2James B. Smadbeck3Julia B. M. Udell4Enrique Garcia-Rivera5Laura Elsbernd6Courtney L. Erskine6George Vasmatzis3Farhad Kosari6Stephen J. Murphy3Hongzheng Ren7Vishnu V. Serla3Janet L. Schaefer Klein3Giannoula Karagouga3Faye R. Harris3Carlos Sosa3Sarah H. Johnson3Wendy Nevala6Svetomir N. Markovic1Aaron O. Bungum2Eric S. Edell2Haidong Dong6,9John C. Cheville7Marie Christine Aubry7Jin Jen8George Vasmatzis1
 
1Division of Medical Oncology, Mayo Clinic, Rochester, MN
2Division of Pulmonary Medicine and Critical Care, Mayo Clinic, Rochester, MN
3Center for Individualized Medicine, Biomarker Discovery Group, Mayo Clinic, Rochester, MN
4Center for International Blood and Marrow Transplant Research, Minneapolis, MN
5nference, Cambridge, MA 02142
6Department of Immunology, Mayo Clinic, Rochester, MN
7Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
8Medical Genome Facility, Mayo Clinic, Rochester, MN
9Department of Urology, Mayo Clinic, Rochester, MN
 
Correspondence: Aaron Mansfield (mansfield.aaron@mayo.edu)
 
Affiliations:
 
Copyright:
Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.