Targeted next-generation sequencing of well-differentiated rectal, gastric, and appendiceal neuroendocrine tumors to identify potential targets

Hum Pathol. 2019 May;87:83-94. doi: 10.1016/j.humpath.2019.02.007. Epub 2019 Mar 6.


Rectal neuroendocrine tumors (NETs) are the most common gastrointestinal (GI) NETs with an uncertain malignant potential despite their small size. There are limited data about driver mutations in rectal NETs, which may explain the tumors' unexpected behavior or common histologic morphology with other GI-NETs. Here, we investigated the clinically and pathologically relevant mutations of rectal and nonrectal NETs and compared the frequency and clinical significance of detected mutations between them. We sequenced 84 primary GI-NETs (69 rectal, 7 gastric, 5 appendiceal, and 3 sigmoid colon NETs) and 3 metastatic GI-NETs using targeted next-generation sequencing. Twenty-one rectal NETs (30.4%) showed at least 1 mutation in 24 cancer-related genes; the most common mutations were TP53 (10.1%) and FBXW7 (7.2%), of which 73% were pathogenic/likely pathogenic mutations. TP53 (p.R337C and p.R213*), PTEN (p.W111*, p.Q214*), CDKN2A (p.W110*), FBXW7 (p.R465H), and AKT1 (p.R23Q) were repetitive mutations found exclusively in rectal NETs, whereas SMAD4 (p.R361C) and STK11 (p.D176N) were repetitive mutations found only in gastric NETs. PTEN (p.G129K), EGFR (p.E709K), and KIT (p.V555I) were shared mutations between rectal and appendiceal NETs, whereas SMAD4 (p.R361C), ALK (p.G1202R), VHL (p.Q132*), and IDH1 (p.R132H) were concurrently detected between rectal and gastric NETs. GI-NETs with higher histologic grades, lymphovascular invasion, or recurrence tended to have higher numbers of mutation variants than other tumors; however, there was no significant difference. In conclusion, rectal NETs commonly carried pathogenic/likely pathogenic mutations. Because most mutations were identified in nonhotspot positions, next-generation sequencing is useful in identifying potential drug targets in rectal NETs.

Keywords: Appendix; Gene set enrichment analysis; Neuroendocrine tumor; Next-generation sequencing; Prognosis; Rectum; Stomach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Appendiceal Neoplasms / genetics*
  • Appendiceal Neoplasms / pathology
  • Child
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / pathology
  • Rectal Neoplasms / genetics*
  • Rectal Neoplasms / pathology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Young Adult