The genomic landscape of small intestine neuroendocrine tumors

Michaela S. Banck, Rahul Kanwar, Amit A. Kulkarni, Ganesh K. Boora, Franziska Metge, Benjamin R. Kipp, Lizhi Zhang, Erik C Thorland, Kay T. Minn, Ramesh Tentu, Bruce W. Eckloff, Eric D Wieben, Yanhong Wu, Julie M Cunningham, David M. Nagorney, Judith A. Gilbert, Matthew M. Ames, Andreas S Beutler

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2502-2508
Number of pages7
JournalJournal of Clinical Investigation
Volume123
Issue number6
DOIs
StatePublished - Jun 3 2013

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Neuroendocrine Tumors
Small Intestine
Nucleotides
Phosphatidylinositol 3-Kinases
Aurora Kinase A
Exome
erbB-1 Genes
Multiple Endocrine Neoplasia Type 1
High-Throughput Nucleotide Sequencing
Neoplasms
Chromatin Assembly and Disassembly
Neoplasm Genes
DNA Damage
Carcinogenesis
Clinical Trials
Apoptosis
Genes
Proteins
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Banck, M. S., Kanwar, R., Kulkarni, A. A., Boora, G. K., Metge, F., Kipp, B. R., ... Beutler, A. S. (2013). The genomic landscape of small intestine neuroendocrine tumors. Journal of Clinical Investigation, 123(6), 2502-2508. https://doi.org/10.1172/JCI67963

The genomic landscape of small intestine neuroendocrine tumors. / Banck, Michaela S.; Kanwar, Rahul; Kulkarni, Amit A.; Boora, Ganesh K.; Metge, Franziska; Kipp, Benjamin R.; Zhang, Lizhi; Thorland, Erik C; Minn, Kay T.; Tentu, Ramesh; Eckloff, Bruce W.; Wieben, Eric D; Wu, Yanhong; Cunningham, Julie M; Nagorney, David M.; Gilbert, Judith A.; Ames, Matthew M.; Beutler, Andreas S.

In: Journal of Clinical Investigation, Vol. 123, No. 6, 03.06.2013, p. 2502-2508.

Research output: Contribution to journalArticle

Banck, MS, Kanwar, R, Kulkarni, AA, Boora, GK, Metge, F, Kipp, BR, Zhang, L, Thorland, EC, Minn, KT, Tentu, R, Eckloff, BW, Wieben, ED, Wu, Y, Cunningham, JM, Nagorney, DM, Gilbert, JA, Ames, MM & Beutler, AS 2013, 'The genomic landscape of small intestine neuroendocrine tumors', Journal of Clinical Investigation, vol. 123, no. 6, pp. 2502-2508. https://doi.org/10.1172/JCI67963
Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR et al. The genomic landscape of small intestine neuroendocrine tumors. Journal of Clinical Investigation. 2013 Jun 3;123(6):2502-2508. https://doi.org/10.1172/JCI67963
Banck, Michaela S. ; Kanwar, Rahul ; Kulkarni, Amit A. ; Boora, Ganesh K. ; Metge, Franziska ; Kipp, Benjamin R. ; Zhang, Lizhi ; Thorland, Erik C ; Minn, Kay T. ; Tentu, Ramesh ; Eckloff, Bruce W. ; Wieben, Eric D ; Wu, Yanhong ; Cunningham, Julie M ; Nagorney, David M. ; Gilbert, Judith A. ; Ames, Matthew M. ; Beutler, Andreas S. / The genomic landscape of small intestine neuroendocrine tumors. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 6. pp. 2502-2508.
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