Comprehensive Genomic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs).

Puccini, Alberto; Poorman, Kelsey; Salem, Mohamed E; Soldato, Davide; Seeber, Andreas; Goldberg, Richard M; Shields, Anthony F; Xiu, Joanne; Battaglin, Francesca; Berger, Martin D.; Tokunaga, Ryuma; Naseem, Madiha; Barzi, Afsaneh; Iqbal, Syma; Zhang, Wu; Soni, Shivani; Hwang, Jimmy J; Philip, Philip A; Sciallero, Stefania; Korn, W Michael; ... (2020). Comprehensive Genomic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs). Clinical cancer research, 26(22), pp. 5943-5951. American Association for Cancer Research 10.1158/1078-0432.CCR-20-1804

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GEP-NENs are rare malignancies with increasing incidence. Their molecular characteristics are still undefined. We explored the underlying biology of GEP-NENs and the differences between gastrointestinal (GI) and pancreatic (PNEN), high-grade (HG), and low-grade (LG) tumors.


GEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), IHC, and in situ hybridization. Tumor mutational burden (TMB) was calculated on the basis of somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci.


In total, 724 GEP-NENs were examined: GI (N = 469), PNEN (N = 255), HG (N = 135), and LG (N = 335). Forty-nine percent were female, and median age was 59. Among LG tumors, the most frequently mutated genes were ATRX (13%), ARID1A (10%), and MEN1 (10%). HG tumors showed TP53 (51%), KRAS (30%), APC (27%), and ARID1A (23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared with HG [MSI-H 0% vs. 4% (P = 0.04), PD-L1 overexpression 1% vs. 6% (P = 0.03), TMB-high 1% vs. 7% (P = 0.05)]. Compared with LG, HG NENs showed a higher mutation rate in BRAF (5.4% vs. 0%, P < 0.0001), KRAS (29.4% vs. 2.6%, P < 0.0001), and PI3KCA (7% vs. 0.3%, P < 0.0001). When compared with GI, PNEN carried higher frequency of MEN1 (25.9% vs. 0.0%, P < 0.0001), FOXO3 (8.6% vs. 0.8%, P = 0.005), ATRX (20.6% vs. 2.0%, P = 0.007), and TSC2 (6.3% vs. 0.0%, P = 0.007), but lower frequency of mutations in APC (1.0% vs. 13.8%, P < 0.0001).


Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Berger, Martin Dave


600 Technology > 610 Medicine & health




American Association for Cancer Research




Rebeka Gerber

Date Deposited:

25 Nov 2020 10:40

Last Modified:

25 Nov 2020 10:40

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