PO-329 Genomic aberration in pancreatic neuroendocrine tumours (PNET)

Abstract

IntroductionRare tumours are poorly investigated and therefore heavily limited in possible therapeutic approaches, and subsequently therapeutic success. One such tumour entity, representing only 1%–2% of all pancreatic malignancies is Pancreatic Neuroendocrine tumours (PNET). PNET are cancers of endocrine cells of the islets of Langerhans and only a handful of studies thus far have investigated the genetic makeup of these tumours. Apart from surgery and chemotherapy for localised tumours, the only approved targeted drug for treatment of advanced PNETs is Everolimus, specifically targeting the mTOR protein. Much is still lacking in the area of targeted therapies and possible options for treating metastasized tumours. Our aim is to therefore establish a genetic profile of PNET tumours in order to determine more targets connected to mTOR signalling and consequently, increase options for improved therapy approaches.Material and methodsWe performed deep coverage sequencing, averaging a depth of 1000 reads, using an established in-house PNET panel. Our cohort included Formaldehyde Fixed Paraffin Embedded (FFPE) patient samples comprising of 50 primary tumours of varying grades, and 14 metastases.Results and discussionsUsing variant calling pipelines, we determined single nucleotide variations (SNV) and copy number variations (CNV) in our cohort and elucidated potential heterogeneity within the PNET tumours. Out of the 62 sequenced samples, 26 primary tumours, and 6 metastases showed SNV alterations with the most recurring being MEN1 alterations (50%) irrespective of whether the tumour is primary or metastasis, followed by DAXX (27%) which was exclusively mutated in primary tumours. In addition, mutation in a novel candidate, polycomb protein EED has been determined specifically in G3 PNET and the alteration falls in one of the β-transducing repeat of the protein. CNV was determined in 38 samples with a recurring copy number increase for RICTOR (~37%). Intra-tumour heterogeneity, based on allelic frequency, is evident in some samples while the combined SNV and CNV profile of these patients reveal a clear inter-tumour heterogeneity in PNETs.ConclusionOur study reveals previously identified and novel alterations, which require further investigation at the protein level to determine new possible therapeutic approaches for PNET patients. In addition, our data clearly reveals that due to the high level of inter-tumour heterogeneity present in these tumours, it is vital to consider a more personalised targeted approach to therapy.