Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma

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 ¼ 22), RNA (n ¼ 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 rearrangementrelated 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.

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

“…Recent work using targeted NGS and high‐density arrays by Mansfield et al using mate‐pair sequencing analyses and a previous study by Yoshikawa et al using targeted NGS in combination with high‐density array comparative genomic hybridization revealed a much higher number of genetic alterations in mesotheliomas than detected by NGS, including point mutations, minute deletions, and copy number changes. NGS is a technique designed to identify point mutations; therefore, larger genetic alterations are easily missed using this technique .…”

HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer

“…Furthermore, DNA library preparation and sequencing approaches may affect the detection of fusions. A recent study identified multiple chromosomal rearrangements that had neoantigenic potential in mesothelioma using mate-pair sequencing 36 whereas prior approaches did not identify many gene fusions. 37,38 Studies have shown that the recognition of neoepitopes by endogenous T cells may elicit protective immune responses without being affected by central T cell tolerance, making neoantigens an ideal target for cancer immunotherapy.…”

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“…Furthermore, insertions and deletions (indels) that result in frameshifts in renal cell carcinoma may be much more immunogenic than nonsynonymous SNV mutations and may not be captured in current TMB estimations (9). Similarly, expression of chromosomal rearrangements may result in neoantigens that are not identified by standard sequencing approaches and are not included in current TMB calculations (10). A more inclusive determination of neoantigenic burden may be a better predictor of response based on the combined mutational signatures (expressed SNVs, indels, chromosomal rearrangements) of the tumors in question.…”