Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic and Notch Pathway Mutations.

Purpose: GI stromal tumors (GISTs) are commonly associated with somatic mutations in and . However, a subset arises from mutations in , most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of alterations in GIST.

Methods: We describe the demographic/clinicopathologic features of 177 patients from two institutions whose GISTs underwent next-generation sequencing of ≥315 cancer-related genes.

Results: We initially identified six (9.7%) of 62 GISTs with genomic alterations from the first cohort. Of these six patients, five (83.3%) had unifocal tumors at the duodenal-jejunal flexure (DJF). Two additional patients with DJF GISTs had non- ( and ) genomic alterations. After excluding one DJF GIST with an single nucleotide polymorphism, four (57.1%) of seven sequenced DJF tumors demonstrated deleterious alterations, whereas only one (1.8%) of 55 sequenced non-DJF GISTs had a deleterious somatic mutation ( < .001). One patient with DJF GIST had a germline variant that was associated with incomplete penetrance of clinical neurofibromatosis type 1 features along with a somatic mutation. Of the five DJF GISTs with any alteration, three (60%) had mutations, and three (60%) had Notch pathway mutations (, , ). We validated these findings in a second cohort of 115 GISTs, where two (40%) of five unifocal -mutated GISTs arose at the DJF, and one of these also had a Notch pathway mutation ().

Conclusion: Broad genomic profiling of adult GISTs has revealed that alterations are enriched in DJF GISTs. These tumors also may harbor concurrent activating and/or inactivating Notch pathway mutations. In some cases, germline genetic testing may be appropriate for patients with DJF GISTs.