RESUMO
HLA-B*58:02:04 differs from HLA-B*58:02:01 by one synonymous nucleotide in codon 215 in exon 4.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Humanos , Alelos , Antígenos HLA-B/genética , Códon , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Background: Neoantigens, mutated tumour-specific antigens, are key targets of anti-tumour immunity during checkpoint inhibitor (CPI) treatment. Their identification is fundamental to designing neoantigen-directed therapy. Non-canonical neoantigens arising from the untranslated regions (UTR) of the genome are an overlooked source of immunogenic neoantigens. Here, we describe the landscape of UTR-derived neoantigens and release a computational tool, PrimeCUTR, to predict UTR neoantigens generated by start-gain and stop-loss mutations. Methods: We applied PrimeCUTR to a whole genome sequencing dataset of pre-treatment tumour samples from CPI-treated patients (n = 341). Cancer immunopeptidomic datasets were interrogated to identify MHC class I presentation of UTR neoantigens. Results: Start-gain neoantigens were predicted in 72.7% of patients, while stop-loss mutations were found in 19.3% of patients. While UTR neoantigens only accounted 2.6% of total predicted neoantigen burden, they contributed 12.4% of neoantigens with high dissimilarity to self-proteome. More start-gain neoantigens were found in CPI responders, but this relationship was not significant when correcting for tumour mutational burden. While most UTR neoantigens are private, we identified two recurrent start-gain mutations in melanoma. Using immunopeptidomic datasets, we identify two distinct MHC class I-presented UTR neoantigens: one from a recurrent start-gain mutation in melanoma, and one private to Jurkat cells. Conclusion: PrimeCUTR is a novel tool which complements existing neoantigen discovery approaches and has potential to increase the detection yield of neoantigens in personalised therapeutics, particularly for neoantigens with high dissimilarity to self. Further studies are warranted to confirm the expression and immunogenicity of UTR neoantigens.
Assuntos
Melanoma , Humanos , Antígenos de Neoplasias/genética , Genes MHC Classe I , Mutação , ImunoterapiaRESUMO
The novel HLA-B*13:191 allele was detected during the HLA typing for kidney transplantation.
Assuntos
Antígenos HLA-B , Transplante de Rim , Humanos , Alelos , Antígenos HLA-B/genética , Genes MHC Classe I , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
HLA-C*06:376N differs from HLA-C*06:02:01:01 by seven nucleotide changes in exon 2, intron 2, and exon 3.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Análise de Sequência de DNA , China , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
The HLA-B*40:538 allele differs from HLA-B*40:01:02:01 at position 905 CâT in exon 5.
Assuntos
Genes MHC Classe I , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Alelos , Éxons/genética , Antígenos HLA-B/genéticaRESUMO
The novel allele HLA-C*07:02:147 differs from HLA-C*07:02:01:01 by one synonymous nucleotide substitution in exon 2.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Éxons/genética , NucleotídeosRESUMO
HLA-C*03:94:02 differs from HLA-C*03:94:01 by a single nucleotide substitution in exon 2 (codon 17 GGA->GGG).
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Sequenciamento de Nucleotídeos em Larga Escala , ChinaRESUMO
Novel HLA-B*55:01:31, HLA-C*07:1113 alleles and confirmatory HLA-C*12:392 allele were detected during the HLA typing process.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Alelos , Antígenos HLA-C/genética , Antígenos HLA-B/genética , Teste de HistocompatibilidadeRESUMO
HLA-C*07:04:29 differs from HLA-C*07:04:01:01 by a single substitution in exon 4.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Alelos , China , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos HLA-C/genética , População do Leste AsiáticoRESUMO
A novel HLA-C*07 allele, now officially designated HLA-C*07:02:150, was identified by next-generation sequencing.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Two nucleotide substitutions in intronic regions give rise to the novel alleles: HLA-B*35:01:01:39 and -B*35:03:01:32.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Humanos , Alelos , Antígenos HLA-B/genética , Íntrons , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
HLA-B*46:01:42 differs from HLA-B*46:01:01:01 by one nucleotide in exon 5.
Assuntos
Genes MHC Classe I , Nucleotídeos , Humanos , Alelos , Antígenos HLA-B/genética , China , Análise de Sequência de DNARESUMO
HLA-B*58:01:40 differs from HLA-B*58:01:01 by a single nucleotide change in exon 3, 507 C- > T (codon 145.3 CGC- > CGT).
Assuntos
Povo Asiático , Genes MHC Classe I , Humanos , Alelos , Povo Asiático/genética , Antígenos HLA-B/genética , ChinaRESUMO
HLA-B*41:02:01:11 and -C*08:266 were detected in a solid organ recipient during the HLA typing process.
Assuntos
Genes MHC Classe I , Genômica , Humanos , Alelos , Antígenos HLA-B/genética , Teste de HistocompatibilidadeRESUMO
Nucleotide substitutions in codons -1 and 84 of HLA-B*40:01:01 result in a novel allele, HLA-B*40:01:35.
Assuntos
Povo Asiático , Genes MHC Classe I , Humanos , Alelos , Povo Asiático/genética , Antígenos HLA-B/genética , NucleotídeosRESUMO
HLA-C*08:273 differs from HLA-C*08:01:01:01 by one nucleotide in exon 2.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Nucleotídeos , China , Análise de Sequência de DNARESUMO
mAbs to MHC class I (MHC-I) molecules have proved to be crucial reagents for tissue typing and fundamental studies of immune recognition. To augment our understanding of epitopic sites seen by a set of anti-MHC-I mAb, we determined X-ray crystal structures of four complexes of anti-MHC-I Fabs bound to peptide/MHC-I/ß2-microglobulin (pMHC-I). An anti-H2-Dd mAb, two anti-MHC-I α3 domain mAbs, and an anti-ß2-microglobulin mAb bind pMHC-I at sites consistent with earlier mutational and functional experiments, and the structures explain allelomorph specificity. Comparison of the experimentally determined structures with computationally derived models using AlphaFold Multimer showed that although predictions of the individual pMHC-I heterodimers were quite acceptable, the computational models failed to properly identify the docking sites of the mAb on pMHC-I. The experimental and predicted structures provide insight into strengths and weaknesses of purely computational approaches and suggest areas that merit additional attention.
Assuntos
Genes MHC Classe I , EpitoposRESUMO
The novel HLA-C*14:159 allele was detected during the routine HLA typing for kidney transplantation.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Sequenciamento de Nucleotídeos em Larga Escala , Teste de HistocompatibilidadeRESUMO
HLA-C*17:01:01:29 differs from the HLA-C*17:01:01:05 allele by one nucleotide substitution in the 3'UTR.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Grécia , Alelos , Regiões 3' não TraduzidasRESUMO
HLA-C*04:01:01:174 differs from the HLA-C*04:01:01:06 allele by one nucleotide substitution in the intron 5.