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Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms

T Vandamme1,2, M Beyens1, G Boons1

  • 1Center of Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.

Endocrine-Related Cancer
|July 20, 2018
PubMed

Insights

Ultra-deep sequencing revealed low-abundance mutations in pancreatic neuroendocrine neoplasms (pNENs), highlighting genetic heterogeneity. This study identified novel mutations and pathways, including the MAPK-ERK pathway, implicating genes like DAXX and ATRX in pNEN development.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Pancreatic neuroendocrine neoplasms (pNENs) are often associated with mutations in DAXX/ATRX, MEN1, and the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.
  • Previous studies primarily identified high-abundance mutations, potentially overlooking low-abundance variants that could drive tumor proliferation.
  • Understanding the full spectrum of genetic alterations in pNENs is crucial for diagnosis and treatment.

Purpose of the Study:

  • To identify both high- and low-abundance mutations in pNENs using ultra-deep targeted resequencing.
  • To investigate genetic intra-tumor heterogeneity in pNENs.
  • To uncover novel genes and pathways involved in pNEN development.

Main Methods:

  • Ultra-deep targeted resequencing of formalin-fixed paraffin-embedded matched tumor-normal tissue from 38 well-differentiated pNENs using a HaloPlex panel.
  • Application of novel amplicon-based algorithms to detect single nucleotide variants (SNVs) and insertion-deletions (indels) at high (>10% reads) and low (<10% reads) abundance.
  • Validation of identified variants using Sanger sequencing.

Main Results:

  • Sequencing generated over 416 million reads with an average coverage of 2663x.
  • 32 high-abundance and 30 low-abundance somatic mutations were identified and validated, with 92% and 84% predicted to be protein-damaging, respectively.
  • Frequently mutated genes included MEN1, DAXX, ATRX, TSC2, and genes in the PI3K/Akt/mTOR and MAPK-ERK pathways. Novel hotspot mutations were found in DAXX, PTCH2, and CYFIP2.

Conclusions:

  • This study demonstrates significant genetic intra-tumor heterogeneity in pNENs, characterized by the presence of low-abundance mutations.
  • The importance of the ATRX/DAXX pathway in pNENs is reinforced, with the discovery of the first pNEN-specific protein-damaging hotspot mutation in DAXX.
  • Novel genes (CYFIP2, PTCH2) and pathways (MAPK-ERK) are implicated in pNEN pathogenesis, opening new avenues for research and therapeutic strategies.
Keywords:
DAXXmolecular geneticsneuroendocrine tumorspancreatic neuroendocrine tumorsultra-deep sequencing

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