Table 1.

Some of the key pathways in Ileal NETs.

Pathway	Gene(s)	Clinical Evidence	Orthologous Evidence	Additional Notes	Key References
Somatostatin receptor-2	SSTR2	Somatostatin analogues approved for treatment of patients with I-NETs	GOT1 cell line responds to somatostatin analogues	SSTR2 is naturally expressed by EC cells.	[17,20,61]
mTOR	mTOR	mTOR inhibitors approved for treatment of patients with I-NETs	GOT1 cell line responds to everolimus	Nonrecurrent CNVs and promoter methylations in mTOR pathway	[20,30,31,32]
IGF2	IGF2	57% of I-NETs show loss of imprinting of IGF2	I-NETs form in RT2B6 and in RT2B6AF2 mice due to IGF2 pathway genes	Pathway downstream of IGF2 is unestablished in I-NETs	[63]
RB1	MIR1-2 CDKN1B CDKN2C	MIR1-2 shows loss of copy in 60% of I-NETs; CDKN1B is mutant in 8%; CDKN2C is mutant in 8%	I-NETs form in mice expressing SV40 T-antigen, which inactivates RB1		[33,34,35,36,69]
p53	MDM2 IPMK	MDM2 overproduction in patient samples; frame-shifted IPMK allele associates with familial I-NETs	I-NETs form in mice expressing SV40 T-antigen; MDM2 inhibitors prevent growth of GOT1	I-NETs often respond poorly to cytotoxic chemotherapies, suggestive of low p53 activity	[74,75,101]