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Study Description

The diagnosed incidence of small bowel neuroendocrine tumors (NETs) is increasing. While patients with localized disease can be treated surgically, those with metastatic disease currently have few treatment options. The success of biologically targeted therapies in other malignancies has led to interest in the molecular alterations underlying the pathogenesis of these NETs. To identify genetic aberrations in small intestine NETs, we generated copy number profiles from 31 primary and metastatic tumors and performed whole-exome sequencing on a subset of 29 primary small intestine NETs and 24 metastatic NETs in parallel with normal blood DNA. Whole-genome sequencing data was generated on 15 tumor/normal pairs and 5 primary/metastasis/normal trios. The global genetic landscape of small bowel NETs is relatively quiet. Consistent with previous studies, the overwhelming majority of tumors were characterized by loss of chromosome 18 and, to a lesser extent, other chromosome arm gains and losses. In stark contrast to arm-level alterations, recurrent high-level focal amplifications and deletions were much less prevalent in these tumors. High-throughput mutation screening and exome sequencing revealed similarly low rates of somatic mutation in NETs (median of 0.77 non-silent mutations per megabase (Mb) of coding DNA) compared to other recent cancer exome sequencing efforts. Our analysis of this cohort identified only a single, statistically significant recurrent somatic mutation targeting the cyclin-dependent kinase inhibitor gene, CDKN1B, encoding p27.

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Study Inclusion/Exclusion Criteria

All samples with a pathological assessment of well-differentiated neuroendocrine tumors of the small intestine or metastasis of the small intestine and a signed informed consent were included as part of the study. Those samples with sufficient native genomic DNA were used for SNP arrays, whole-exome or whole-genome sequencing. Samples were removed from analysis when there was a poor concordance between tumor and normal SNPs. Samples that did not meet whole-exome capture and/or sequencing requirements were also removed from the analysis.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Exome Sequencing Illumina HiSeq 2000 N/A N/A
Whole-genome sequencing Illumina HiSeq 2000 N/A N/A
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Study Attribution
  • Principal Investigator
    • Matthew Meyerson, MD, PhD. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA, USA.
    • Matthew Kulke, MD. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA, USA.
  • Funding Source
    • Caring for Carcinoid Foundation, Boston, Massachusetts, USA.
    • Raymond and Beverly Sackler Foundation for the Arts and Sciences, New York, NY, USA.