Classification of neoantigen sources in cancer: genomic, transcriptomic, and proteomic alterations
| Category | Mechanism | Description | Neoantigen impact | References |
|---|---|---|---|---|
| Genomic mutations | Single nucleotide variants (SNVs) | A single-base substitution causes amino acid changes. | Alters the coding sequence, generating novel peptides. | [60] |
| Insertions and deletions (INDELs) | Small insertions or deletions lead to frameshift mutations. | Frameshift mutations alter amino acid sequences and generate novel open reading frames (ORFs). | [61, 62] | |
| Gene fusions | Fusion of two genes creating a chimeric protein. | Generates unique antigenic epitopes due to the formation of hybrid peptides. | [63] | |
| Viral sequences and endogenous retroviruses (ERVs) | Integration/reactivation of viral sequences in the genome. | Introduces foreign protein-coding sequences, producing immunogenic peptides. | [64, 65] | |
| Transcriptomic variants | Constitutive splicing | Standard intron removal and exon joining. | Preserves the normal coding sequence, minimal neoantigen impact. | [66, 67] |
| Exon skipping/inclusion | Variable inclusion or exclusion of exons. | Modifies the protein structure, potentially generating novel peptide regions. | [68, 69] | |
| Alternative 5' and 3' splice sites | Variations in donor and acceptor splice site selection. | Shifts exon boundaries, altering peptide sequence diversity. | [70, 71] | |
| Intron retention | Failure to remove an intron during splicing. | The translation of non-coding regions can introduce premature stop codons and novel antigenic sites. | [72, 73] | |
| Mutually exclusive exons | Expression of one exon while excluding another. | Generates diverse protein isoforms with unique antigenic determinants. | [74, 75] | |
| Exitrons | Hybrid exonic-intronic regions where introns are partially retained. | Alters the final protein product, increasing peptide diversity. | [76, 77] | |
| Adenosine-to-inosine (A-to-I) RNA editing | Post-transcriptional modification converting adenosine to inosine. | Alters codons without changing the underlying genomic sequence, leading to novel peptide generation. | [78, 79] | |
| Proteomic variants | ORFs | Translation initiated from previously untranslated regions. | Produces peptides not expressed under normal conditions, expanding neoantigen diversity. | [80, 81] |
| Coding long non-coding RNAs (lncRNAs) | Some lncRNAs can generate small peptides. | Generates small immunogenic peptides despite being non-coding. | [82, 83] | |
| Defective translation | Translational errors such as frameshifts or premature termination. | Produces aberrant protein fragments, expanding the neoantigen repertoire. | [84] | |
| Alternative start sites | Translation initiated from non-canonical codons (CUG, AGG, AUA). | Generates alternative protein isoforms with novel N-terminal sequences. | [85, 86] | |
| Post-translational modifications | Modifications like phosphorylation, glycosylation, ubiquitination. | Alters peptide structure and may expose hidden epitopes for immune recognition. | [87, 88] |