Association Between Human Leukocyte Antigen Class I and II Diversity and Non-virus-associated Solid Tumors

Liu, Zhiwei; Hildesheim, Allan

doi:10.3389/fgene.2021.675860

Cited by 8 publications

(8 citation statements)

References 14 publications

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“…A previous study showed no association between HLA heterozygosity and the risk of 12 non-virus-associated solid tumours. 31 The heterogeneity in study design might contribute to the different results. The result comparison of previous studies and this study was compared in Supplementary Table S13 .…”

Section: Discussionmentioning

confidence: 99%

Association of HLA diversity with the risk of 25 cancers in the UK Biobank

Wang¹,

Wang²,

Deng³

et al. 2023

eBioMedicine

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Section: Discussionmentioning

confidence: 99%

Association of HLA diversity with the risk of 25 cancers in the UK Biobank

Wang¹,

Wang²,

Deng³

et al. 2023

eBioMedicine

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“…We next investigated HLA homozygosity frequencies in EUR patients in comparison with values reported in control individuals ( 75 ). Among HLA class I genes, homozygosity frequencies ranged from 10% (Ewing sarcoma) to 20% (nephroblastoma) for HLA-A , from none (HGG, ependymoma, nephroblastoma) to 7.5% (osteosarcoma) for HLA-B , and from 3.8% (HGG) to 12.2% (NRSTS) for HLA-C , as compared to 14.8, 6.7 and 9.4% of controls, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…The percentages of patients homozygous for HLA class I and II genes are indicated in cohorts corresponding to specific tumor types (A) and subtypes (B) . Reference frequencies reported in EUR control individuals ( 75 ) are shown on the left (grey bar; NA: not available). The label in the upper left corner of each panel refers to the corresponding HLA gene.…”

Section: Resultsmentioning

confidence: 99%

Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers

Lim,

Marques Da Costa,

Godefroy

et al. 2024

Front. Immunol.

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The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing (TAP) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers.

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Section: Discussionunclassified

“…Homozygosity at HLA loci might lead to reduced immunosurveillance and increased disease risk, while this mechanism is particularly evident for cancers with a high mutational load and/or infectious or autoimmune etiologies, 32 our study does not support a strong role for HLA zygosity on risk of NB in line with other studies focused on non-virus-associated solid tumours. 71 Our study specifically addresses a subset of European populations, an approach required for precise ancestry matching of cases and controls. This matching is a deliberate strategy to reduce biases in our association analyses.…”

Section: Hla-dqb1mentioning

confidence: 99%

Exploring the role of HLA variants in neuroblastoma susceptibility through whole exome sequencing

Bonfiglio,

Lasorsa,

Aievola

et al. 2024

HLA

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Although a number of susceptibility loci for neuroblastoma (NB) have been identified by genome‐wide association studies, it is still unclear whether variants in the HLA region contribute to NB susceptibility. In this study, we conducted a comprehensive genetic analysis of variants in the HLA region among 724 NB patients and 2863 matched controls from different cohorts. We exploited whole‐exome sequencing data to accurately type HLA alleles with an ensemble approach on the results from three different typing tools, and carried out rigorous sample quality control to ensure a fine‐scale ancestry matching. The frequencies of common HLA alleles were compared between cases and controls by logistic regression under additive and non‐additive models. Population stratification was taken into account adjusting for ancestry‐informative principal components. We detected significant HLA associations with NB. In particular, HLA‐DQB1*05:02 (OR = 1.61; padj = 5.4 × 10−3) and HLA‐DRB1*16:01 (OR = 1.60; padj = 2.3 × 10−2) alleles were associated to higher risk of developing NB. Conditional analysis highlighted the HLA‐DQB1*05:02 allele and its residue Ser57 as key to this association. DQB1*05:02 allele was not associated to clinical features worse outcomes in the NB cohort. Nevertheless, a risk score derived from the allelic combinations of five HLA variants showed a substantial predictive value for patient survival (HR = 1.53; p = 0.032) that was independent from established NB prognostic factors. Our study leveraged powerful computational methods to explore WES data and HLA variants and to reveal complex genetic associations. Further studies are needed to validate the mechanisms of these interactions that contribute to the multifaceted pattern of factors underlying the disease initiation and progression.

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Association Between Human Leukocyte Antigen Class I and II Diversity and Non-virus-associated Solid Tumors

Cited by 8 publications

References 14 publications

Association of HLA diversity with the risk of 25 cancers in the UK Biobank

Association of HLA diversity with the risk of 25 cancers in the UK Biobank

Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers

Exploring the role of HLA variants in neuroblastoma susceptibility through whole exome sequencing

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