Neuroendocrine tumours

The challenge with large scale sequencing data is determining which variants are pathogenic. The NET GeCIP will select novel NEN variants for further analysis, using our previously reported algorithm to identify variants in genes associated with hereditary endocrine diseases (1). Approximately 20% of all NENs are due to hereditary syndromes, with at least 24 genes implicated in driving NEN tumourigenesis. Recent work by Scarpa and colleagues (2017) showed that 17% of pancreatic NENs have germline mutations in well characterised genes such as Menin, VHL, MUTYH and BRCA2 which can be easily screened for using next generation sequencing panels.

Many of the genes known to be associated with hereditary syndromes are also mutated in sporadic NENs, for example >40% of pancreatic NENs have a mutation in the MEN1 gene, that causes multiple endocrine neoplasia type 1, in which patients develop NENs predominantly in the pituitary, parathyroid and pancreas. Our algorithm takes into account the frequency, evolutionary conservation, segregation and predicted functional effects of the variant, and therefore, will be applicable to variants occurring in hereditary and sporadic NENs.