Identification of new candidate genes and signalling pathways associated with the development of neuroendocrine pancreatic tumours based on next generation sequencing data.

Despite advances in classification, treatment, and imaging, neuroendocrine tumours remain a clinically complex subject. In this work, we studied the genetic profile of well-differentiated pancreatic neuroendocrine tumours (PanNETs) in a cohort of Caucasian patients and analysed the signalling pathways and candidate genes potentially associated with the development of this oncological disease. Twenty-four formalin-fixed paraffin-embedded (FFPE) samples of well-differentiated PanNETs were subjected to massive parallel sequencing using the targeted gene panel (409 genes) of the Illumina NextSeq 550 platform (San Diego, USA). In 24 patients, 119 variants were identified in 54 genes. The median mutation rate per patient was 5 (2.8-7). The detected genetic changes were dominated by missense mutations (67%) and nonsense mutations (29%). 18% of the mutations were activating, 35% of the variants led to a loss of function of the encoded protein, and 52% were not classified. Twenty-six variants were described as new. Functionally significant changes in the tertiary structure and activity of the protein molecules in an in silico assay were predicted for 5 new genetic variants. The 5 highest priority candidate genes were selected: CREB1, TCF12, PRKAR1A, BCL11A, and BUB1B. Genes carrying the identified mutations participate in signalling pathways known to be involved in PanNETs; in addition, 38% of the cases showed genetic changes in the regulation of the SMAD2/3 signalling pathway. Well-differentiated PanNETs in a Russian cohort demonstrate various molecular genetic features, including new genetic variations and potential driver genes. The highlighted molecular genetic changes in the SMAD2/3 signalling pathway suggest new prospects for targeted therapy.