scholarly journals 1100MO Molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

2021 ◽  
Vol 32 ◽  
pp. S910-S911
Author(s):  
H. Sorbye ◽  
A. Venizelos ◽  
H. Elvebakken ◽  
A. Perren ◽  
I.M.B. Lothe ◽  
...  
Keyword(s):  
Molecular Characteristics ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms

scholarly journals The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

2021 ◽  
Author(s):  
Andreas Venizelos ◽  
Hege Elvebakken ◽  
Aurel Perren ◽  
Oleksii Nikolaienko ◽  
Wei Deng ◽  
...  
Keyword(s):  
Copy Number ◽  
Primary Tumour ◽  
Treatment Strategies ◽  
Morphological Differentiation ◽  
Molecular Characteristics ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Braf Mutations ◽  
Molecular Features ◽  
Net G3

High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on sequencing of 360 cancer related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). 8/152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicates a high potential for better personalized treatments.

scholarly journals 1170P The prognostic role of DLL3 expression in high-grade gastroenteropancreatic neuroendocrine neoplasms

2020 ◽  
Vol 31 ◽  
pp. S776
Author(s):  
C. Liverani ◽  
A. Bongiovanni ◽  
L. Mercatali ◽  
F. Pieri ◽  
C. Spadazzi ◽  
...  
Keyword(s):  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Prognostic Role ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms

scholarly journals Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

2021 ◽  
Vol 10 (8) ◽  
pp. 1741
Author(s):  
Giovanni Centonze ◽  
Vincenzo Lagano ◽  
Giovanna Sabella ◽  
Alessandro Mangogna ◽  
Giovanna Garzone ◽  
...  
Keyword(s):  
T Cell ◽  
Multivariable Analysis ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Immune Markers ◽  
Cancer Specific Survival ◽  
Ki 67 ◽  
Clinical Databases ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Net G3

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61–28.33, p < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.

scholarly journals Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4463
Author(s):  
Katharina M. Detjen ◽  
Raik Otto ◽  
Yvonne Giesecke ◽  
Lukas Geisler ◽  
Pamela Riemer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Tumor Tissue ◽  
Treatment Decisions ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Patient Stratification ◽  
Term Survival ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Related Survival

Background: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. Methods: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN. Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients’ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue. Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.

scholarly journals 29 Elevated Flt3L predicts long-term survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A34-A34
Author(s):  
Katharina Detjen ◽  
Raik Otto ◽  
Yvonne Giesecke ◽  
Lukas Geisler ◽  
Pamela Riemer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Tissue ◽  
Surrogate Marker ◽  
Ethics Committee ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Patient Stratification ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Ethical Approval ◽  
Related Survival

BackgroundGastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are a rare and heterogeneous family of tumors arising from the disseminated neuroendocrine system of the gastrointestinal tract and pancreas. Clinical management of high-grade GEP-NEN is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable stratification of patients with otherwise comparable tumor features.MethodsWe used RNAseq data from human foregut-derived pancreatic and gastric GEP-NEN to evaluate Flt3L gene expression in tumor tissue. The data set (n=54) represented the full range of NEN grades and differentiation, and expression levels were compared to healthy control tissue as well. We also analyzed circulating Flt3L levels in serum samples of a separate cohort of G2/G3 GEP-NEN (n=59) an healthy controls (n=4). The study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.ResultsWe detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted disease related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients´ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue.ConclusionsOur results suggest Flt3L as a surrogate marker of an inflammatory tumor microenvironment. Therefore, we propose Flt3L as a prognostic biomarker for high grade GEP-NEN. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, may hold the promise to guide patient stratification and tailor treatment decisions and should be further evaluated, especially in the context of immunotherapies.Ethics ApprovalThe study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.

Sign in / Sign up

Export Citation Format

Share Document