Abstract 1164P
Background
MiRNAs regulate many biological processes including the hallmarks of cancer. They have been identified as potential biomarkers for cancer diagnosis, prognosis and as therapeutic targets, but few studies have assessed their role in NENs. The aim of this study was to characterize the miRNA profile in a large cohort of NENs and assess their correlation with clinical-pathological (CP) features and prognostic value in this setting.
Methods
84 cancer-related miRNAs were analyzed by PCR Array technology. For each patient, the relative quantification of normalized miRNA’s expression was obtained by 2 -ΔΔCtmethod (tumor and paired-normal samples). CP variable distribution was assessed using parametric or non-parametric tests as appropriate. K-M method and long-rank test were used to assess the prognostic value of categorical variables. Multivariate Cox regression model was performed to evaluate the independent prognostic value of selected miRNAs, adjusted for age, primary tumor site, grade and stage. MiRNAs that showed independent prognostic value including multitest adjustment (FDR) were selected. Hierarchical clustering using miRNA expression and euclidean distance of the selected miRNAs was performed. 3 public databases (TargetScan Release, miRDB and Diana-Tarbase) were used to predict miRNA’s biological targets. An in silico functional analysis (R clusterProfiler) was then performed to identify enriched pathways using Hallmarks and KEGG gene set collections from MsigDB.
Results
86 NEN samples (51 Lung, 35 GEP) were analyzed: 51% G1 or TC, 19% G2 or AC and 30% G3 NEC. 40 miRNAs were significantly associated with different CP features. Among them, we identified a signature of 8 miRNAs with independent prognostic value (P<0,05). Our signature identified 3 distinct prognostic groups, with 5-year OS of 97%, 64% and 39%, respectively. Oncogenic pathways regulated by these miRNAs included NFKβ, RAS, WNT/β-catenin, TGFβ, PI3K-AKT-mTOR and P53.
Conclusions
Our study has identified a novel 8-miRNAs signature able to predict OS of GEP and lung NENs, independent of other well stablished prognostic factors. These miRNAs regulate critical oncogenic pathways that could potentially be explored as novel targets for therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Imas12.
Funding
Imas12.
Disclosure
P. Espinosa-Olarte: Travel/Accommodation/Expenses, Travel expenses for academic purposes: Ipsen; Travel/Accommodation/Expenses, Travel expenses for academic purposes: Novartis; Travel/Accommodation/Expenses, Travel expenses for academic purposes: Pfizer. M. Benavent: Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Novartis. P. Jimenez-Fonseca: Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy: AAA; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Leo Pharma; Speaker Bureau/Expert testimony: HRApharma. M.C. Riesco-Martinez: Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Bayer, Novartis; Travel/Accommodation/Expenses, Travel expenses for academic purposes: Servier; Non-remunerated activity/ies: Incyte Biocience. R. Garcia-Carbonero: Honoraria (self), Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: AAA, Advanz Pharma, Bayer, BMS, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Sanofi and Servier; Research grant/Funding (institution): Pfizer, BMS; Research grant/Funding (self), Research grant/Funding (institution): ARMO BioSciences, AstraZeneca, Pfizer, Novartis, Ipsen, Roche, Pharmacyclics, Boston Biomedicals, Merck, MSD, Amgen, Sanofi, Bayer, Bristol-Myers-Squibb, Boehringer, Sysmex, Gilead Sciences, Servier, Adacap, VCN, Lilly, PharmaMar; Non-remunerated activity/ies: Member of the Executive Committee of the Spanish Neuroendocrine Tumor Cooperative Group (GETNE), Member of the Executive Committee of the European Society of Neuroendocrine Tumors (ENETS), Member of the Scientific Advisory Group for Oncology (SAG-O) of th; Leadership role, Research grant/Funding (institution): Global PI of a clinical trial of Axitinib (Pfizer) in NETs; Global PI of a clinical trial of Nivolumab (BMS) and chemotherapy in NECs; Non-remunerated activity/ies: Member of the EORTC, ASCO, ESMO, SEOM, TTD, GEMCAD. All other authors have declared no conflicts of interest.