Optical genome mapping identifies a novel PSIP1::TBL1X fusion in metastatic pancreatic neuroendocrine tumors

Abstract

Background and aimsEffective treatment of metastatic neuroendocrine tumors (NETs) is limited by a lack of targeted therapies and clinically useful predictive biomarkers. We applied complementary genomic profiling technologies to identify genomic alterations that could lead to actionable drug targets and biomarkers. MethodsOptical genome mapping (OGM) and whole exome sequencing (WES) were performed on 70 liver metastases of neuroendocrine tumors from multiple anatomical primary sites. PacBio Iso-Seq long read sequencing and western blotting was used to confirm fusion gene expression. Findings were validated by rtPCR and western blotting on a separate cohort of 17 resection specimens from 14 pancreatic NET cases. ResultsSomatic variant calling from OGM data detected recurrent fusions involving TBL1X (PSIP1::TBL1X) and BEND2 (CHD7::BEND2 and NEO1::BEND2) in pancreatic neuroendocrine tumors (pNETs). BEND2 fusions were associated with high grade tumors, as previously described. The novel PSIP1::TBL1X fusion was confirmed to result in fusion transcript expression by both long-read sequencing and nested rtPCR. Presence of the PSIP1::TBL1X fusion transcript was also confirmed in a second cohort of pNET resection specimens and fusion protein expression was established by western blotting. Both TBL1X and BEND2 fusions are mutually exclusive with ATRX/DAXX mutations. ConclusionThis study underscores the importance of structural variants, including fusion genes as both prognostic biomarkers and potential therapeutic targets, especially in ATRX/DAXX negative pNETs. BEND2 fusion positivity may be a clinically useful biomarker for aggressive disease. As all TBL1X fusion isoforms contain the entire TBL1X coding sequence, TBL1X inhibition could be explored as a novel treatment for TBL1X fusion positive pNETs.