Most of the neoantigens are believed to be derived from passenger gene mutations. However, recent progress in human tumor studies has revealed that neoantigens derived from driver gene mutations could generate common and shared neoantigens in certain cases.
IDH1 R132H yields aberrant oncometabolite and induces gliomas, as observed in CD4
+ T cells in patients and humanized mice carrying HLA-DRB1*01:01
[58]. This mutation-targeting peptide vaccine could elicit intratumoral inflammation in most patients harboring multiple HLA alleles
[59]. Immunoglobulin-variable regions of lymphoma cells presented on HLA-DR*04:01 are recognized by cytotoxic CD4
+ T cells
[60]. H3.3 K27M mutation, which results in aberrant gene expression, is the cause of most diffuse intrinsic pontine glioma, and acts as the target of HLA-A2 restricted CD8
+ T cells
[61]. Frameshift mutant NPM1, which is frequently observed in acute myeloid leukemia, binds to HLA-A*02:01
[62]. Therefore, the TCR from the responding T cells was cloned. Moreover, TP53, a well-known mutated gene in many cancer types, was expressed on HLA-A*02:01 (R175H) and HLA-A*68:01 (R248W) (MHC-I) and HLA-DRB1*13:01 (R175H) and HLA-DRB3*02:02 (Y220C) and HLA-DPB*02:01 (R248W) (MHC-II)
[63][64]. TCR against the mutated position of TP53 R175H has already been cloned and validated to recognize many kinds of tumors containing this same mutation
[65]. Other famous driver mutations, KRAS G12D and G12V, were recognized by CD8
+ and CD4
+ T cells, respectively, in the specific alleles
[66][67][68]. In addition, the other driver mutant PIK3CA and c-Kit are immunogenic in healthy donors
[69]. Driver mutations are necessary to maintain tumor cell characteristics; therefore, more aggressive metastatic pancreatic cancers can harbor uniform gene mutations, thus supporting the shared neoantigens as strong therapeutic targets
[70]. Missense and indel mutation-derived neoantigens are not limited, but fusion gene products, typically neighboring joint sequences, have recently been identified as tumor neoantigens even in tumors with low mutation burden tumors
[71][72]. Fusion gene products are thought to be frequently involved in tumorigenesis
[73]. Hence, fusion genes have become important in the novel neoantigen landscape for immunotherapy as well as driver mutation loci. These studies strongly suggest that NGS mapping should be performed over classical systems solely focusing on the exome to identify neoantigens. Beyond personalized medicine, shared neoantigens can become the primary choice for vaccine targets and neoantigen-specific TCR therapy.