Finding Molecular Subgroups of Worse Prognosis Studying the Microenvironment of Gastro-Entero-Pancreatic Neuroendocrine Tumours (Gep-Net).

Abstract

ABSTRACT Aim: Tumour suppressor genes, CDKN1B and PTEN, are commonly altered in GEP-NET. However, their role is not completely understood yet. The aim of this study was to link the expression of their products (p27 and PTEN) with proteins of the GEP-NET microenvironment. Methods: Formalin-fixed and paraffin-embedded samples (FFPEs) of patients (pts) who underwent surgery for GEP-NET and their clinical data were collected consecutively from 1980 to 2012. The study was approved by the local Ethics Committee. Tissue microarrays were constructed from non-necrotic areas of tumour foci. We performed a stratified analysis of proteins related to the extracellular matrix and the epithelial to mesenchymal transition process by inmunohistochemistry-measured PTEN and P27. Kaplan-Meier method and log rank test was used for the univariate survival analysis and Cox regression was used for the multivariate analysis (MSA). Results: A total of 115 FFPEs were analysed. Median follow up was 12 years. Median age was 46 years; 49.6% female; 67.8% intestinal. PTEN was evaluated as presence vs absence and P27 as strong nuclear staining vs weak or absence. P27 and PTEN were independent prognostic factors for disease free survival (DFS) when adjusted by grade and stage, p = 0.028 and p = 0.023 respectively. Within the PTEN negative subgroup, LOXL2 + conferred protection for relapse, p CXCR4 + CXCR4- LOXL2 + LOXL2- BCATm BCATn P27- 55.9 (0.1-132.8) NR NR 7.2 (4.6-7.8) NR 124.1 (16.7-231.5) PTEN- NC NC NR 0.4 (0.1-2.2) NR 124.1 (35.3-212.9) DFS medians calculated in months by Kaplan Meier method. BCATm: b-catenin membranous staining. NR: not reached. NC: not calculated. Conclusions: Patients with P27– LOXL2– or PTEN– LOXL2– had the worst prognosis. These findings warrant further in vitro mechanistically experiments and prospective clinical analysis. Disclosure: All authors have declared no conflicts of interest.