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

Ha Young Park, Mi Jung Kwon, Ho Suk Kang, Yun Joong Kim, Nan Young Kim, Min Jeong Kim, Kyueng Whan Min, Kyung Chan Choi, Eun Sook Nam, Seong Jin Cho, Hye Rim Park, Soo Kee Min, Jinwon Seo, Ji Young Choe, Hye Kyung Lee

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)83-94
Number of pages12
JournalHuman Pathology
Volume87
DOIs
StatePublished - 2019 May

Keywords

  • Appendix
  • Gene set enrichment analysis
  • Neuroendocrine tumor
  • Next-generation sequencing
  • Prognosis
  • Rectum
  • Stomach

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    Park, H. Y., Kwon, M. J., Kang, H. S., Kim, Y. J., Kim, N. Y., Kim, M. J., Min, K. W., Choi, K. C., Nam, E. S., Cho, S. J., Park, H. R., Min, S. K., Seo, J., Choe, J. Y., & Lee, H. K. (2019). Targeted next-generation sequencing of well-differentiated rectal, gastric, and appendiceal neuroendocrine tumors to identify potential targets. Human Pathology, 87, 83-94. https://doi.org/10.1016/j.humpath.2019.02.007