Johns Hopkins Pancreatic Neuroendocrine Tumor Exome Sequencing

Overview

Whole-exome sequencing study of 68 sporadic, non-familial pancreatic neuroendocrine tumors (PanNETs) from Johns Hopkins University and Memorial Sloan Kettering Cancer Center. The study used a two-stage design: 10 tumors for whole-exome discovery (Illumina GAIIx with SureSelect capture, mean 101x coverage) and 58 additional tumors for targeted Sanger validation. Familial syndrome-associated tumors and small cell/large cell neuroendocrine carcinomas were excluded. All tumors were microdissected to >80% neoplastic cellularity.

Composition

  • Cancer type: PANET
  • 68 sporadic PanNETs: 10 discovery (WES) + 58 validation (Sanger)
  • Key clinical fields: survival, stage, grade, Ki-67 index, metastatic status
  • Assays: whole-exome-seq (discovery set) and sanger-sequencing (validation set)

Assays / panels (linked)

Papers using this cohort

  • PMID:21252315 — Jiao et al. 2011, exome sequencing of PanNETs identifying MEN1/DAXX/ATRX driver landscape

Notable findings derived from this cohort

  • MEN1 mutated in 44.1% (30/68) of PanNETs; 25/30 mutations were inactivating (indels, nonsense, splice-site) PMID:21252315
  • DAXX mutated in 25% and ATRX in 17.6%; mutations were mutually exclusive; combined DAXX/ATRX pathway alteration rate 42.6% PMID:21252315
  • mTOR pathway genes mutated in 14%: PTEN 7.3%, TSC2 8.8%, PIK3CA 1.4% PMID:21252315
  • MEN1 and DAXX/ATRX mutations associated with significantly better prognosis: 100% survival at 10 years vs. >60% mortality within 5 years in mutation-negative patients PMID:21252315
  • PanNETs have a distinct genetic landscape from pancreatic ductal adenocarcinoma: KRAS 0% and TP53 3% in PanNETs vs. ~100% and ~85% in PDAC PMID:21252315
  • Mean 16 somatic mutations per tumor; 91% of discovery-set mutations validated by Sanger sequencing PMID:21252315

Sources

  • PMID:21252315 — Jiao et al., “DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors,” Science 2011

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