Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic <i>NF1</i> and Notch Pathway Mutations.
retrospective_cohort · Level III
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- Record sourced from PubMed, PMID 29938249.
- Also identified by DOI 10.1200/PO.17.00014 and PMC identifier 6013064.
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Abstract
GI stromal tumors (GISTs) are commonly associated with somatic mutations in <i>KIT</i> and <i>PDGFRA</i>. However, a subset arises from mutations in <i>NF1</i>, most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of <i>NF1</i> alterations in GIST. We describe the demographic/clinicopathologic features of 177 patients from two institutions whose GISTs underwent next-generation sequencing of ≥315 cancer-related genes. We initially identified six (9.7%) of 62 GISTs with <i>NF1</i> 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-<i>NF1</i> (<i>KIT</i> and <i>BRAF</i>) genomic alterations. After excluding one DJF GIST with an <i>NF1</i> single nucleotide polymorphism, four (57.1%) of seven sequenced DJF tumors demonstrated deleterious <i>NF1</i> alterations, whereas only one (1.8%) of 55 sequenced non-DJF GISTs had a deleterious <i>NF1</i> somatic mutation (<i>P</i> < .001). One patient with DJF GIST had a germline <i>NF1</i> variant that was associated with incomplete penetrance of clinical neurofibromatosis type 1 features along with a somatic <i>NF1</i> mutation. Of the five DJF GISTs with any <i>NF1</i> alteration, three (60%) had <i>KIT</i> mutations, and three (60%) had Notch pathway mutations (<i>NOTCH2</i>, <i>MAML2</i>, <i>CDC73</i>). We validated these findings in a second cohort of 115 GISTs, where two (40%) of five unifocal <i>NF1</i>-mutated GISTs arose at the DJF, and one of these also had a Notch pathway mutation (<i>EP300</i>). Broad genomic profiling of adult GISTs has revealed that <i>NF1</i> alterations are enriched in DJF GISTs. These tumors also may harbor concurrent activating <i>KIT</i> and/or inactivating Notch pathway mutations. In some cases, germline <i>NF1</i> genetic testing may be appropriate for patients with DJF GISTs.