Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes

Castro, Andrea; Öztürk, Kıvılcım; Pyke, Rachel Marty; Su, Xian; Zanetti, Maurizio; Carter, Hannah

doi:10.1186/s12920-019-0544-1

Cited by 74 publications

(73 citation statements)

References 29 publications

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“…Given reports of greater mutational burden and corresponding neoantigen levels among tumors with somatic HLA gene mutations [ 11 ], we performed a subanalysis evaluating mutation load among the aforementioned four patients with HLA-B and/or HLA-C -mutant tumors, compared with the rest of the cohort. All four patients had greater than the cohort-average number of mutations, and the two patients whose tumors harbored co-occurring HLA-B and HLA-C mutations (Patient# 2 and 14) had significantly higher number of mutations (n = 554 and 193, compared to cohort average of 83; Fig.…”

Section: Resultsmentioning

confidence: 99%

A pilot radiogenomic study of DIPG reveals distinct subgroups with unique clinical trajectories and therapeutic targets

Zhu

Lazow

Schafer

et al. 2021

acta neuropathol commun

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An adequate understanding of the relationships between radiographic and genomic features in diffuse intrinsic pontine glioma (DIPG) is essential, especially in the absence of universal biopsy, to further characterize the molecular heterogeneity of this disease and determine which patients are most likely to respond to biologically-driven therapies. Here, a radiogenomics analytic approach was applied to a cohort of 28 patients with DIPG. Tumor size and imaging characteristics from all available serial MRIs were evaluated by a neuro-radiologist, and patients were divided into three radiographic response groups (partial response [PR], stable disease [SD], progressive disease [PD]) based on MRI within 2 months of radiotherapy (RT) completion. Whole genome and RNA sequencing were performed on autopsy tumor specimens. We report several key, therapeutically-relevant findings: (1) Certain radiologic features on first and subsequent post-RT MRIs are associated with worse overall survival, including PD following irradiation as well as present, new, and/or increasing peripheral ring enhancement, necrosis, and diffusion restriction. (2) Upregulation of EMT-related genes and distant tumor spread at autopsy are observed in a subset of DIPG patients who exhibit poorer radiographic response to irradiation and/or higher likelihood of harboring H3F3A mutations, suggesting possible benefit of upfront craniospinal irradiation. (3) Additional genetic aberrations were identified, including DYNC1LI1 mutations in a subgroup of patients with PR on post-RT MRI; further investigation into potential roles in DIPG tumorigenesis and/or treatment sensitivity is necessary. (4) Whereas most DIPG tumors have an immunologically “cold” microenvironment, there appears to be a subset which harbor a more inflammatory genomic profile and/or higher mutational burden, with a trend toward improved overall survival and more favorable radiographic response to irradiation, in whom immunotherapy should be considered. This study has begun elucidating relationships between post-RT radiographic response with DIPG molecular profiles, revealing radiogenomically distinct subgroups with unique clinical trajectories and therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

A pilot radiogenomic study of DIPG reveals distinct subgroups with unique clinical trajectories and therapeutic targets

Zhu

Lazow

Schafer

et al. 2021

acta neuropathol commun

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“…It has been suggested that the presence of a highquality neoantigen is required for response to therapy [32] while a high burden of neoantigens has been associated with impaired anti-tumor immune activity [33]; thus, we focused on neoantigen quality over quantity by using patient minimum PHBR score (i.e., best-presented mutation) to predict whether mutations observed in a patient's tumor are likely to generate effectively presented neoantigens. We assessed the ability of PHBR and TMB to predict response to ICB in diverse solid tumors.…”

Section: Introductionmentioning

confidence: 99%

MHC-I genotype and tumor mutational burden predict response to immunotherapy

et al. 2020

Self Cite

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Background: Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB. Methods: Comprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient. Results: The median progression-free survival (PFS) for PHBR score < 0.5 vs. ≥ 0.5 was 5.1 vs. 4.4 months (P = 0.04). Using a TMB cutoff of 10 mutations/mb, the stable disease > 6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients. Conclusions: Poor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.

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“…However, somatic mutations in HLA-I are relatively infrequent in TCGA, varying from below 1% incidence in BRCA and GBM, to around 5% in BLCA, LUAD and SKCM, and up to 10% in HNSC 8,35 . Using a comprehensive list of HLA-I mutations in TCGA 38 , we identified 22 nonsense HLA-I mutations in our cohort in the following subtypes (Supplementary Table 1):…”

Section: Assessment Of Allele-specific Expression Loss (Ase Loss)mentioning

confidence: 99%

HLA allele-specific expression loss in tumors can shorten survival and hinder immunotherapy

Filip

Orenbuch

Zhao

et al. 2020

Preprint

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Efficient presentation of aberrant peptide fragments by the human leukocyte antigen class I (HLA-I) genes is necessary for immune detection and killing of cancer cells. Patient HLA-I genotypes are known to impact the efficacy of cancer immunotherapy, and the somatic loss of HLA-I heterozygosity has been established as a factor in immune evasion. While global deregulated expression of HLA-I has been reported in different tumor types, the role of HLA-I allele-specific expression loss - that is, the preferential RNA expression loss of specific HLA-I alleles - has not been fully characterized in cancer. In the present study, we quantified HLA-I allele-specific expression (ASE) across eleven TCGA tumor types using a novel method from input RNA and whole-exome sequencing data. Allele-specific loss in at least one of the three HLA-I genes (ASE loss) was pervasive and associated to worse overall survival across tumor types, including pancreatic adenocarcinomas, prostate carcinomas and glioblastomas, among others. In particular, our analysis shows that detection of neoantigens with binding affinity to the specific HLA-I genes subject to ASE loss was a top prognostic indicator of overall survival. Additionally, we found that ASE loss hindered immunotherapy in retrospective analyses. Together, these results highlight the prevalence of HLA-I ASE loss - a previously uncharacterized phenomenon in cancer - and provide initial evidence of its clinical significance in cancer prognosis and immunotherapy treatment.

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Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes

Cited by 74 publications

References 29 publications

A pilot radiogenomic study of DIPG reveals distinct subgroups with unique clinical trajectories and therapeutic targets

A pilot radiogenomic study of DIPG reveals distinct subgroups with unique clinical trajectories and therapeutic targets

MHC-I genotype and tumor mutational burden predict response to immunotherapy

HLA allele-specific expression loss in tumors can shorten survival and hinder immunotherapy

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