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.

Keywords: angiogenesis; genetic mutation; mTOR pathway; neuroendocrine tumor.

Figure 1

All gene mutations identified in the 40 Taiwanese patients with pancreatic neuroendocrine tumors (pNETs). The yellow, blue, green, red, purple, and gray color represent gene involved the DAXX/ATRX, MEN1, mTOR, angiogenesis, TP53, and miscellaneous pathway, respectively.

Figure 2

Kaplan-Meier overall survival curves for patients with pNETs, stratified by the status of (a) WHO grade, (b) ATXX/DAXX mutations, and (c) MEN1-pathway gene mutations.

Figure 2

Kaplan-Meier overall survival curves for patients with pNETs, stratified by the status of (a) WHO grade, (b) ATXX/DAXX mutations, and (c) MEN1-pathway gene mutations.

Figure 2

Kaplan-Meier overall survival curves for patients with pNETs, stratified by the status of (a) WHO grade, (b) ATXX/DAXX mutations, and (c) MEN1-pathway gene mutations.