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<p>About 40% of non-functioning (NF) Pancreatic Neuroendocrine Tumors (PanNETs) harbour mutations in <i>MEN1</i>, often co-occurring with <i>DAXX/ATRX.</i> While the ADM group (<i>MEN1</i> and <i>DAXX/ATRX</i> co-mutated) exhibits homogeneous genetic and epigenetic features and a consistent risk of relapse, it shows considerable variability in treatment response, suggesting an underlying molecular diversity. In this study we aimed to elucidate the molecular mechanisms underlying this heterogeneity of ADM PanNETs by integrating transcriptomic (<i>n</i> = 36) and DNA methylation (<i>n</i> = 93) data. First, DNA methylation discriminates ADM-PanNET from PanNET mutated only in <i>MEN1</i> (α-like), revealing enhancer, peri-centromeric, and telomeric methylation changes associated with alternative lengthening of telomeres and increased chromosomal instability. Transcriptomic analysis further revealed three distinct ADM subtypes: ADM hypoxic, ADM NST (No Special Type), and ADM immunosuppressive. The ADM hypoxic subtype is characterized by strong hypoxia signature, likely regulated epigenetically. The ADM NST subtype appears to be primarily driven by epigenetic changes that promote proliferation. Notably, the ADM immunosuppressive subtype, although significantly smaller (&lt; 2.5&#xa0;cm, <i>p</i> = 0.023), exhibits strong immune and metastasis-like signatures, suggesting a uniquely aggressive biology despite its reduced size. By defining these three novel ADM subtypes, our study provides a refined framework for understanding PanNET heterogeneity. This classification underscores potential diagnostic markers and highlights distinct biological vulnerabilities that may inform the development of subtype-tailored therapeutic strategies.</p>

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Molecular Subtypes of Pancreatic Neuroendocrine Tumors Mutated in MEN1/DAXX/ATRX Explain Biological Variability

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Simona Avanthay,
  • Annunziata Di Domenico,
  • Philipp Kirchner,
  • Konstantin Bräutigam,
  • Aziz Chouchane,
  • Renaud Maire,
  • Christina Thirlwell,
  • Corina Kim-Fuchs,
  • Aurel Perren,
  • Ilaria Marinoni

摘要

About 40% of non-functioning (NF) Pancreatic Neuroendocrine Tumors (PanNETs) harbour mutations in MEN1, often co-occurring with DAXX/ATRX. While the ADM group (MEN1 and DAXX/ATRX co-mutated) exhibits homogeneous genetic and epigenetic features and a consistent risk of relapse, it shows considerable variability in treatment response, suggesting an underlying molecular diversity. In this study we aimed to elucidate the molecular mechanisms underlying this heterogeneity of ADM PanNETs by integrating transcriptomic (n = 36) and DNA methylation (n = 93) data. First, DNA methylation discriminates ADM-PanNET from PanNET mutated only in MEN1 (α-like), revealing enhancer, peri-centromeric, and telomeric methylation changes associated with alternative lengthening of telomeres and increased chromosomal instability. Transcriptomic analysis further revealed three distinct ADM subtypes: ADM hypoxic, ADM NST (No Special Type), and ADM immunosuppressive. The ADM hypoxic subtype is characterized by strong hypoxia signature, likely regulated epigenetically. The ADM NST subtype appears to be primarily driven by epigenetic changes that promote proliferation. Notably, the ADM immunosuppressive subtype, although significantly smaller (< 2.5 cm, p = 0.023), exhibits strong immune and metastasis-like signatures, suggesting a uniquely aggressive biology despite its reduced size. By defining these three novel ADM subtypes, our study provides a refined framework for understanding PanNET heterogeneity. This classification underscores potential diagnostic markers and highlights distinct biological vulnerabilities that may inform the development of subtype-tailored therapeutic strategies.