The genomic landscape of small intestine neuroendocrine tumors

J Clin Invest. 2013 Jun;123(6):2502-8. doi: 10.1172/JCI67963. Epub 2013 May 15.

Abstract

Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0-0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Exome
  • Genes, Neoplasm
  • Genomics
  • Humans
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / mortality
  • Mutation
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / mortality
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins c-akt / genetics
  • RNA Splice Sites
  • Sequence Analysis, DNA
  • Signal Transduction / genetics

Substances

  • RNA Splice Sites
  • AKT1 protein, human
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt

Associated data

  • GEO/GSE45190