Chromosomal rearrangements and their neoantigenic potential in mesothelioma

Aaron Scott Mansfield, Tobias Peikert, George Vasmatzis

Abstract

Chromosomal rearrangements are a defining molecular feature of mesothelioma that are not readily detected by standard DNA sequencing approaches but could be detected by whole genome sequencing methods such as mate-pair sequencing. These chromosomal rearrangements result in novel, unique gene junctions that can be expressed and potentially result in the presentation of several neoantigens. These predicted neoantigens can be presented by tumors on major histocompatibility complex (MHC) proteins and are correlated with clonal expansion of tumor infiltrating T cells. T cells responsive to these neoantigens have been identified in the circulation of a patient. The predictive values of next generation sequencing-based tumor mutation burden measurements may be significantly enhanced by the addition of techniques such as mate-pair sequencing that can detect chromosomal rearrangements. Furthermore, rearrangement associated neo-antigens may also represent valuable targets for future anti-tumor vaccine strategies. Finally, chromosomal rearrangements are now recognized as a mutation signature in cancer and these events are likely to be important in the oncogenesis and immune recognition of not only in mesothelioma but multiple malignancies including non-small cell lung cancer.