Unravelling the RNA landscape of small intestine neuroendocrine neoplasms applying transcriptomic and spliceosomic perspectives (A09)

Introduction: The study of small intestine neuroendocrine neoplasms (siNENs) transcriptomics represents a challenge due to their rarity, tissue availability, and heterogeneity. Recent studies identified different molecular subtypes, but there are still gaps in the molecular mechanisms driving siNEN progression.

Aim(s): To evaluate the spliceosomic landscape – splicing factors and variants – in a set of 44 siNENs to identify putative biomarkers related to clinical features.

Materials and methods: We analysed a set of 44 siNEN paraffin-embedded samples using RNAseq. Gene expression and splicing variants were analysed using Cufflinks tools and SUPPA2, respectively. Clinical data were collected, including location, treatment, chromogranin A secretion, Ki-67 index, metastasis, overall survival, among others. Poor outcome was defined as death within the first 5 years from diagnosis.

Results: We quantified transcripts derived from 9.348 unique genes and analysed more than 160.000 splicing variants. Concerning the splicing machinery, we identified 14 genes whose expression differed between short- and long-term survivors. In addition, the expression of 3 factors was related to chromogranin A secretion and liver metastases. Interestingly, we identified 90 differentially spliced variants that diverged between short- and long-term survivors, 2 of them being linked to Ki-67 index or chromogranin A secretion. Enrichment analyses highlighted cell differentiation and migration pathways.

Conclusion: Analysis of the splicing machinery and splicing variants enables the identification of altered genes and variants associated with specific clinical features, thus paving the way to enhance our understanding of siNEN heterogeneity and guiding future research to develop personalized targeted therapeutic strategies.

Keywords: small intestine neuroendocrine neoplasm, splicing, transcriptomics, biomarker