title: The genomic landscape of small intestine neuroendocrine tumors.
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.
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA. banck.michaela@mayo.edu
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Banck
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanwar
authors.forename: Amit A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Boora
authors.forename: Franziska
authors.initials: F
authors.lastname: Metge
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Kipp
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.forename: Erik C
authors.initials: EC
authors.lastname: Thorland
authors.forename: Kay T
authors.initials: KT
authors.lastname: Minn
authors.forename: Ramesh
authors.initials: R
authors.lastname: Tentu
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Eckloff
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieben
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: David M
authors.initials: DM
authors.lastname: Nagorney
authors.forename: Judith A
authors.initials: JA
authors.lastname: Gilbert
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Beutler
mesh_terms: D001483:Base Sequence; D059472:Exome; D052138:Genes, Neoplasm; D023281:Genomics; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000401:mortality; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D022821:RNA Splice Sites; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics
chemical_list: D022821:RNA Splice Sites; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt