Profiling of GEPNETs

Table 1

Summary of genomic profiling studies on pancreatic neuroendocrine tumors (PNETs).

Study	Tumor type (number)	Profiling platform	Main findings	Therapeutic implications
Jonkers et al. [28] Cytogenet Genome Res	Sporadic insulinoma (𝑛=30) (15 benign, 8 uncertain behaviour, 7 malignant)	Array CGH (BAC array, 3.700 clones)	Chromosomal instability (CIN) (≥20 chromosomal alterations/tumor) and telomeric losses (≥6 losses/tumor) correlate with malignant progression Loss of 22q11.21–13.31 and gain of 7p21.1–11.2 correlate with malignant behaviour	Candidate genes for targeted therapy in regions of chromosomal gains include MAD2L1, CDC4, GCK, BRAF, KRAS, KNTC1, CK19, BRCA1, and BCL2
Jonkers et al. [31] J Pathol	Sporadic insulinoma (𝑛=27) (15 benign, 6 uncertain behaviour 6 malignant)	Array CGH (BAC array, and 3.700 clones)	Gain of 9q32 and loss of 22q13.1 are early events in tumorigenesis. Loss of 11q24.1 and 22q13.31 is associated with advanced tumor stage	Candidate genes for targeted therapy in regions of chromosomal gains include ShcC
Nagano et al. [35] Endocr Relat Cancer	PNET (𝑛=15) (14 sporadic, 1 MEN1; 13 NF-PNET, 2 gastrinomas; 9 WDNC, 6 WDNT UMP)	SNP-array (Affymetrix, 50K)	Loss on chromosomes 1, 3, 11, 22. Gains on chromosomes 5, 7, 12, 14, 17, and 20.	Candidate genes for targeted therapy in regions of chromosomal gains include TERT, EGFR, IGFBP-3, CDK6, and RET
Hu et al. [39] Genes Cancer	PNET (𝑛=55)	Array CGH (Agilent, 44K)	Loss on chromosomes 1, 2, 7, 10, 11, 16, 17, 19, 20, and 22. Gain on chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 17, and 18.	Targeting amplified genes, including MDM2, MDM4, and WIP1
Jiao et al. [41] Science	Sporadic PNET (𝑛=68)	NGS (exome) (Illumina)	Mutations in MEN1 (44%), DAXX/ ATRX (43%), PTEN (7%), TSC2 (9%), and PIK3CA (1%). Tumors with mutations in MEN1 and/or DAXX/ATRX are associated with prolonged survival	Targeting mTOR pathway

For genes and proteins in bold, therapeutic agents are available for preclinical or clinical testing. BAC: bacterial artificial chromosome; CGH: comparative genomic hybridisation; F-PNET: functioning PNET; NF-PNET: non-functioning PNET; NGS: next-generation sequencing; PNET: pancreatic neuroendocrine tumor; SNP: single-nucleotide polymorphism; WDNC: well-differentiated neuoendocrine carcinoma; WDNT UMP: well-differentiated neuroendocrine tumor of uncertain malignant potential.