Genes involved in angiogenesis and mTOR pathways are frequently mutated in Asian patients with pancreatic neuroendocrine tumors.

Abstract

Introduction: To address the issue of limited data on and inconsistent findings for genetic alterations in pancreatic neuroendocrine tumors (pNETs), we analyzed sequences of known pNET-associated genes for their impact on clinical outcomes in a Taiwanese cohort. Methods: Tissue samples from 40 patients with sporadic pNETs were sequenced using a customized sequencing panel that analyzed 43 genes with either an established or potential association with pNETs. Genetic mutations and clinical outcomes were analyzed for potential associations. Results: Thirty-three patients (82.5%) survived for a median 5.9 years (range, 0.3-18.4) of follow up. The median number of mutations per patient was 3 (range, 0-16). The most frequent mutations were in ATRX (28%), MEN1 (28%), ASCL1 (28%), TP53 (20%), mTOR (20%), ARID1A (20%), and VHL (20%). The mutation frequencies in the MEN1 (including MEN1/PSIP1/ARID1A), mTOR (including mTOR/PIK3CA/AKT1/PTEN /TS1/TSC2/ATM), DAXX/ATRX, and angiogenesis (including VHL/ANGPT1/ANGPT2 /HIF1A) pathways were 48%, 48%, 38%, and 45%, respectively. Mutations in ATRX were associated with WHO grade I pNET (vs. grade II or III, p = 0.043), and so were those in genes involved in angiogenesis (p = 0.002). Patients with mutated MEN1 and DAXX/ATRX pathways showed a trend toward better survival, compared to patients with the wild-type genes (p = 0.08 and 0.12, respectively). Conclusion: Genetic profiles of Asian patients with pNETs were distinct from Caucasian patient profiles. Asian patients with pNETs were more frequently mutated for the mTOR and angiogenesis pathways. This could partially explain the better outcome observed for targeted therapy in Asian patients with pNETs.

• Authors: Wen-Chi Chou, Po-Han Lin, Yi-Chen Yeh, Yi-Ming Shyr, Wen-Liang Fang, Shin-E Wang, Chun-Yu Liu, Peter Mu-Hsin Chang, Ming-Han Chen, Yi-Ping Hung, Chung-Pin Li, Yee Chao, Ming-Huang Chen
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 12 Issue 12 Pg. 1523-1532 ( 2016) ISSN: 1449-2288 [Electronic] Australia
• PMID: 27994516 (Publication Type: Journal Article)

Chemical References

• ARID1A protein, human
• ASCL1 protein, human
• Basic Helix-Loop-Helix Transcription Factors
• DNA-Binding Proteins
• Nuclear Proteins
• TP53 protein, human
• Transcription Factors
• Tumor Suppressor Protein p53
• Von Hippel-Lindau Tumor Suppressor Protein
• MTOR protein, human
• TOR Serine-Threonine Kinases
• DNA Helicases
• ATRX protein, human
• X-linked Nuclear Protein
• VHL protein, human

Topics

• Adolescent
• Asian People
• Basic Helix-Loop-Helix Transcription Factors (genetics)
• Child
• Child, Preschool
• DNA Helicases (genetics)
• DNA-Binding Proteins
• Female
• Humans
• Infant
• Male
• Multiple Endocrine Neoplasia Type 1 (genetics)
• Mutation (genetics)
• Neovascularization, Pathologic (genetics)
• Neuroendocrine Tumors (genetics)
• Nuclear Proteins (genetics)
• Pancreatic Neoplasms (genetics)
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Transcription Factors (genetics)
• Tumor Suppressor Protein p53 (genetics)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)
• X-linked Nuclear Protein