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The genomic landscape of small intestine neuroendocrine tumors
Michaela S. Banck, … , Matthew M. Ames, Andreas S. Beutler
Michaela S. Banck, … , Matthew M. Ames, Andreas S. Beutler
Published May 15, 2013
Citation Information: J Clin Invest. 2013;123(6):2502-2508. https://doi.org/10.1172/JCI67963.
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Research Article Oncology

The genomic landscape of small intestine neuroendocrine tumors

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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.

Authors

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

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Figure 1

Tumor and sequencing characteristics.

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Tumor and sequencing characteristics.
Tumor-associated (somatic) mutatio...
Tumor-associated (somatic) mutations in the exome were determined by nextgen sequencing. (A) Sequencing quality control. Total raw sequencing reads and enrichment for the targeted exome regions were similar across samples. Quality control measures were uncorrelated with downstream results, supporting that observed disparities among tumors represent biological diversity of SI-NETs. x axes in A, C, E, and G correspond to individual tumors. (B) Survival of 48 patients. See also Supplemental Figure 2. (C) Tumor cell purity was determined by histopathology, VAF (fraction of mutated sequencing reads), and copy number alteration estimates (based on the ratio of sequence read counts for a tumor-deleted chromosome compared with germline). The 3 methods cross-validated the observation that mean tumor content was high across the dataset and uncorrelated with biological results. (D) Formalin-fixed, paraffin-embedded (FFPE) and frozen sections of 2 cases, demonstrating tumor purity and well-differentiated histology. (E) Ki-67 labeling index, demonstrating that the majority of cases were WHO 2010 classification low grade (≤2%), and a minority were intermediate grade (>3%). See also Supplemental Figure 3. (F) Ki-67 immunohistochemistry for cases in D. Numerals indicate the Ki-67 index. (G) Mutation counts and VAF for individual tumors. The number of mutations is shown for each patient as a scatter plot of the VAF for each event. While the sensitivity of sequencing technology detecting alterations in subsets of tumor cells is limited by sequence read depth, the distribution of VAF suggests that the reported mutations are dominant throughout the entirety of each tumor. (H) Unimodal distribution of VAF among mutation calls. Original magnification, ×40.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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