The genomic landscape of small intestine neuroendocrine tumors
Michaela S Banck1, Rahul Kanwar, Amit A Kulkarni
1Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA. banck.michaela@mayo.edu
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.
Insights
Small intestine neuroendocrine tumors (SI-NETs) are genetically stable but harbor alterations in key cancer genes. Exome sequencing identified actionable therapeutic targets and deregulated pathways, enabling potential patient grouping for personalized treatment.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Small intestine neuroendocrine tumors (SI-NETs) represent the most frequent small bowel malignancy.
- Targeting PI3K/Akt/mTOR signaling is a focus of clinical trials, but the genetic landscape of SI-NETs remains largely unexplored.
Purpose of the Study:
- To investigate the underlying genetic alterations in SI-NETs using comprehensive exome sequencing.
- To identify potential therapeutic targets and deregulated pathways for improved patient stratification.
Main Methods:
- Massively parallel exome sequencing of 48 SI-NET samples.
- Analysis of somatic single nucleotide variants (SNVs) and copy number variations.
- Integrative analysis to identify recurrently altered carcinogenesis mechanisms.
Main Results:
- SI-NETs exhibit genetic stability with a low mutation rate.
- 197 protein-altering SNVs affected significant cancer genes (e.g., FGFR2, MEN1, EZH2).
- Recurrently altered pathways include chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance.
- Actionable alterations were identified in 35 patients, with PI3K/Akt/mTOR pathway alterations (AKT1/AKT2 amplification) in 16 patients.
Conclusions:
- Exome sequencing reveals a distinct genetic profile for SI-NETs.
- Identified genetic alterations provide opportunities for targeted therapies and patient stratification.
- Sequencing-based analysis can facilitate provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.
