Pancreatic Neuroendocrine Tumor (PANET)

Overview

Pancreatic neuroendocrine tumors (PanNETs / PANET) are rare epithelial neoplasms arising from islet cells of the pancreas. They sit at OncoTree level 2 under the PANCREAS lineage. PanNETs have a distinct genetic landscape from pancreatic ductal adenocarcinoma (PDAC): KRAS and TP53, nearly universally altered in PDAC, are rarely mutated in PanNETs. Recurrent mutations in chromatin-remodeling genes (MEN1, DAXX, ATRX) and the mTOR pathway define the molecular landscape of sporadic PanNETs.

Cohorts in the corpus

  • 68 sporadic, non-familial PanNETs (discovery set n=10, validation set n=58) from Johns Hopkins and Memorial Sloan-Kettering Cancer Center; small cell and large cell neuroendocrine carcinomas excluded; dataset panet_jhu_2011. PMID:21252315

Recurrent alterations

  • MEN1: inactivating mutations (indels, nonsense, splice-site) in 44.1% (30/68) of PanNETs; biallelic inactivation documented; encodes menin, a component of MLL/SET1-like histone methyltransferase complexes. PMID:21252315
  • DAXX: inactivating mutations in 25% (17/68); loss of immunolabeling correlates with mutation status; H3.3-specific histone chaperone. PMID:21252315
  • ATRX: inactivating mutations in 17.6% (12/68); missense mutations cluster in the conserved helicase domain; partners with DAXX for H3.3 incorporation at telomeres. DAXX and ATRX mutations are mutually exclusive (combined pathway rate 42.6%). PMID:21252315
  • TSC2: mutations in 8.8% (6/68); mTOR pathway negative regulator. PMID:21252315
  • PTEN: mutations in 7.3% (5/68); mTOR pathway tumor suppressor. PMID:21252315
  • PIK3CA: mutations in 1.4% (1/68); mTOR/PI3K pathway. PMID:21252315
  • Overall mTOR pathway alteration rate: 14%; mean somatic mutation burden 16 per tumor (range 8–23), ~60% fewer than PDAC. PMID:21252315
  • Whole-genome and transcriptome analysis (WGTA) of 10 metastatic pancreatic NENs (PanNENs) in the POG cohort confirmed recurrent MEN1, DAXX, ATRX, RB1, and TP53 alterations; MEN1-mutant PanNENs (but not PulNENs) showed large-scale LOH. Actionable alterations were identified in the majority of cases, with MTOR-inhibitor (everolimus), somatostatin analogs, and CDKN2A/CDK4/6-inhibitor recommendations supported by genomic findings. Median TMB was 2.19 mut/Mb across the full 28-patient NEN cohort. PMID:24326773

Subtypes

  • Chromatin-mutated subtype: MEN1 and/or DAXX/ATRX mutations; associated with prolonged survival — in metastatic cases with both MEN1 and DAXX/ATRX mutations, 100% survived ≥10 years vs. >60% death within 5 years in mutation-negative patients. PMID:21252315
  • mTOR-activated subtype: PTEN/TSC2/PIK3CA mutations (~14%); provides genetic rationale for everolimus treatment. PMID:21252315

Therapeutic landscape

  • mTOR pathway mutations (14% of PanNETs) support stratification for treatment with everolimus (RAD-001); RADIANT-3 trial demonstrated increased progression-free survival in advanced PanNET patients. PMID:21252315

Sources

  • PMID:21252315 — Jiao et al. (2011), whole-exome sequencing of 68 sporadic PanNETs identifying recurrent MEN1, DAXX, and ATRX mutations.

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This page was processed by crosslinker on 2026-05-09.