Table 3.

Molecular profiling studies revealing PI3K-Akt-mTOR signaling pathway alterations in pNETs.

Technique	Reference	Key Findings
Exome sequencing	[24]	Somatic PTEN, TSC2, and PIK3CA mutations in 7.3%, 8.8%, and 1.4% of 68 sporadic pNETs, respectively.
	[23]	Somatic mutations in mTOR pathway genes observed in 102 primary pNETs: PTEN (7%), DEPDC (2%), TSC1 (2%), and TSC2 (2%). mTOR pathway gene mutations associated with poor survival.
	[40]	11% of 65 pNETs had mTOR pathway gene mutations: TSC2 (6%) and PTEN (5%).
	[43]	TSC2 mutations in 25% of 80 patient pNETs. In total, 1 of 17 patients carried a germline TSC2 mutation.
Allelotyping/LOH analysis	[87]	LOH of 10q23 (where PTEN is located) in >50% of 22 pNETs. PTEN mutations rarely observed.
	[86]	Allelic deletions of 16p13 (where TSC2 is located) in 36% of 28 pNETs
Microarray	[88]	TSC2, PTEN or both downregulated in 85% of primary PNETs, subsequently validated by qRT-PCR and IHC studies. Reduced expression of TSC2 and PTEN correlated with poor patient prognosis.
RNA sequencing	[106]	Ingenuity pathway analysis (IPA) and Connectivity Map (CMap) analysis of 626 metastatic gene signatures obtained from 39 primary tumors, 21 lymph node metastases and 17 liver metastases predicted mTOR and PI3K as top pNET pharmacological targets.
	[92]	Alteration of Akt signaling genes revealed by sequencing of 20 primary pNETs.
IHC	[107]	Low PTEN expression in 48% of 21 pNETs.