Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with different prognosis. Clinical and pathological factors are used to predict outcome but there are some patients that have a poor outcome even with good classical prognostic factors. We aimed to define a different RNA expression profile (EP) that could detect patients with worse prognosis and identify possible targetable new pathways.
We identified 48 paraffin-embedded archival tumor material of patients with metastatic grade 1/2 NENs of small intestine origin for RNAseq. We generated on average 66 million paired-end reads for each sample on HiSeq2500 (Illumina). RNAseq reads were mapped against the human reference genome (hg19) with Tophat (v2.0.14) and quantified using Cufflinks tools suite (v.2.2.1). 41 samples had sufficient quality to be included in the analysis. We used multivariate Cox proportional models to study the association between EP, clinical variables (gender, age, location of metastases, hormone production and Ki67 index) and overall survival (OS). We defined as poor outcome those patients that died within the first 3 years of the diagnosis of advanced disease.
9348 transcripts were quantified. A gene signature of 329 transcripts was defined by a two-way statistical analysis between poor and long term survivors. A pathway enrichment analysis of these genes showed a deregulation in the poor prognosis group on the PI3KCA-Akt-mTOR and the Toll-like receptor signaling pathways. The hazard ratio (HR) for mOS defined by EP comparing poor and long term survivor groups was 0.33, 95% CI 0.1-1.1, p = 0.081 in the univariate analysis and HR of 0.05, 95% CI 0.005-0.51, p = 0.011 in the multivariate analysis.
We identified statistically different RNA-clusters and different deregulated pathways for those patients with advanced NENs of small intestine origin with poor prognosis. To our knowledge, this is the first time that Toll-like pathway is involved in the pathogenesis of NENs. These results are relevant as they may help improve the prognosis stratification of patients and involve novel targetable pathways of great clinical potential.
Clinical trial identification
Legal entity responsible for the study
Vall d’Hebron Institute of Oncology
Spanish Task Force for Neuroendocrine and Endocrine Tumors (GETNE)
All authors have declared no conflicts of interest.