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 10 6 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. IntroductionSmall intestine neuroendocrine neoplasms (SI-NENs) are the most common malignancy of the small bowel, represent the largest group of NENs by organ site, and are studied in clinical treatment trials targeting PI3K/Akt/mTOR signaling. Whether this or other canonical cancer pathways is recurrently mutated, however, is uncertain, because a genome-wide, unbiased sequence analysis of cancer genes has not been performed to date in SI-NENs.Massively parallel, or "nextgen," DNA sequencing is currently advancing research in other human malignancies by facilitating the collection of comprehensive, genome-wide, unbiased datasets providing a common data framework for comparing results across different tumor types and gene sets. It provides the most comprehensive technology to date to explore the potential of genomics for individualizing cancer treatment within a tumor type. To unlock and explore the potential of the technology for translational research in SI-NEN, we sequenced 48 such tumors.

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

“…Our findings are supported by previous studies showing that besides stromal cells, human primary PanNET and metastatic cells express high levels of PDGFRβ compared with normal tissue (51,52). Moreover, clinical reports show evidence of PDGFR activation and copy number alteration in small intestine, gastroenteropancreatic, and pancreatic NET, although the use of whole tumor cell lysates precludes identification of the cell type expressing PDGFRβ (21,53). The identification of PDGFRβ + tumor cells in human PanNET has important clinical implications, considering that sunitinib, a PDGFR/VEGFR small molecule inhibitor, was recently approved to treat patients with progressive well-differentiated PanNET (54).…”

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

“…Strikingly, the exact same GO terms were enriched for miR-143, GO:0042981 'regulation of apoptosis' (Benjamini-Hochberg P = 0.049), GO:0043067 'regulation of programmed cell death' (BenjaminiHochberg P = 0.033) and GO:0010941 'regulation of cell death' (Benjamini-Hochberg P = 0.025). Target genes encompassed by these GO terms for both miRNAs included those normally upregulated in oncogenesis, such as NUAK2 (Namiki et al 2011), EGFR (copy number gain seen in 4% SBNETs (Banck et al 2013)), KRAS, NRAS, IGF1 , Reidy-Lagunes et al 2012, MAPK1 (ERK1) , BCL2, ARHGEF7 and BMP7 (Supplementary Table 4). Target genes specific only for miR-1 included HGF (Svejda et al 2013) and VEGFA.…”

Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum

“…Furthermore, in a series of 48 SI-NETs, 22 had mutations or deletions in genes (Banck et al 2013). This underlines the importance of the TGFβ signalling pathway in SI-NETs.…”

“…Endocrine-Related Cancer pathway in a subset of these tumours, inhibition of PDGF signalling is potentially an attractive therapeutic target (Banck et al 2013).…”