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Peer-reviewedCC BY 4.0Frontiers in Immunology

Human leucocyte antigen class I and II alleles are associated with tumor susceptibility in neurofibromatosis type 1

  • Jonathan H. Sussman1,2,3,4
  • Stephanie N. Brosius1,2
  • Bernat Gel5,6
  • Peiyao Li1,2
  • Alvin Farrel1,2
  • Jo Lynne Rokita7,8
  • Eduard Serra9,10
  • Kai Tan1,2
  • Michael J. Fisher1,2
  • John M. Maris1,2
  • Thomas De Raedt1,2
10 affiliations
  1. 1Department of Pediatrics, Division of Oncology, Children’s Hospital of Philadelphia
  2. 2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine
  3. 3Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania
  4. 4Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania
  5. 5Departament de Fonaments Clínics, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB)
  6. 6Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
  7. 7Center for Cancer and Immunology Research, Children’s National Hospital
  8. 8Department of Pediatrics, The George Washington University School of Medicine and Health Sciences
  9. 9Translational Genomics and Bioinformatics of Cancer, Germans Trias i Pujol Research Institute (IGTP)
  10. 10Hereditary Cancer Group, Germans Trias i Pujol Research Institute (IGTP)
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Abstract

Introduction: Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic tumor predisposition syndrome. NF1 patients display remarkable phenotypic variability, even within families carrying the same NF1 mutation. With few exceptions, the identification of specific genotype-phenotype correlations has remained elusive.

Methods: We utilized RNA-sequencing, whole exome sequencing data and direct DNA sequencing to determine HLA genotypes for individuals with NF1-associated high-grade glioma (HGG, n=38), low-grade glioma (LGG, n=91), and malignant peripheral nerve sheath tumors (MPNST, n=105). Odds ratios (OR), binomial p-values and false discovery values were calculated by comparing observed carrier frequencies against expected frequencies derived from ethnicity-matched population data.

Results: We find that specific HLA class I and II alleles are associated with different NF1 tumor types. For example, HLA-B*40:02 is significantly associated with NF1-MPNST (OR=3.71, p=0.001, Q=0.023), increasing the lifetime risks for MPNST from 10-15.8% to about 36.6% (CI 16.1-57.2%).

Discussion: The relative cancer risk for an individual in the general population carrying a risk allele can be high, however, that individual's absolute risk for cancer typically remains very low. In contrast, individuals that carry a risk allele and are also burdened with a tumor predisposition syndrome will have a substantially higher absolute risk to develop a tumor, simply because they start at a higher baseline susceptibility for tumors. The identification of HLA-risk alleles for NF1 tumor development has the potential to improve clinical care and outcomes by prompting risk-adapted screening and treatment. It is important to note that the associations found in this study require validation in an independent prospective cohort.

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Cite

BibTeXRIS
BibTeX
@article{sussman2026human,
  title = {{Human leucocyte antigen class I and II alleles are associated with tumor susceptibility in neurofibromatosis type 1}},
  author = {Jonathan H. Sussman and Stephanie N. Brosius and Bernat Gel and Peiyao Li and Alvin Farrel and Jo Lynne Rokita and Eduard Serra and Kai Tan and Michael J. Fisher and John M. Maris and Thomas De Raedt},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1966259},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1966259/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Human leucocyte antigen class I and II alleles are associated with tumor susceptibility in neurofibromatosis type 1
AU  - Jonathan H. Sussman
AU  - Stephanie N. Brosius
AU  - Bernat Gel
AU  - Peiyao Li
AU  - Alvin Farrel
AU  - Jo Lynne Rokita
AU  - Eduard Serra
AU  - Kai Tan
AU  - Michael J. Fisher
AU  - John M. Maris
AU  - Thomas De Raedt
PY  - 2026
DA  - 2026/10/19
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1966259
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1966259/full
AB  - Introduction: Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic tumor predisposition syndrome. NF1 patients display remarkable phenotypic variability, even within families carrying the same NF1 mutation. With few exceptions, the identification of specific genotype-phenotype correlations has remained elusive.  Methods: We utilized RNA-sequencing, whole exome sequencing data and direct DNA sequencing to determine HLA genotypes for individuals with NF1-associated high-grade glioma (HGG, n=38), low-grade glioma (LGG, n=91), and malignant peripheral nerve sheath tumors (MPNST, n=105). Odds ratios (OR), binomial p-values and false discovery values were calculated by comparing observed carrier frequencies against expected frequencies derived from ethnicity-matched population data.  Results: We find that specific HLA class I and II alleles are associated with different NF1 tumor types. For example, HLA-B*40:02 is significantly associated with NF1-MPNST (OR=3.71, p=0.001, Q=0.023), increasing the lifetime risks for MPNST from 10-15.8% to about 36.6% (CI 16.1-57.2%).  Discussion: The relative cancer risk for an individual in the general population carrying a risk allele can be high, however, that individual's absolute risk for cancer typically remains very low. In contrast, individuals that carry a risk allele and are also burdened with a tumor predisposition syndrome will have a substantially higher absolute risk to develop a tumor, simply because they start at a higher baseline susceptibility for tumors. The identification of HLA-risk alleles for NF1 tumor development has the potential to improve clinical care and outcomes by prompting risk-adapted screening and treatment. It is important to note that the associations found in this study require validation in an independent prospective cohort.
SN  - 1664-3224
ER  -