Whole exomes sequencing for neurofibromatosis type I patients complicated with gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. 85% GISTs carry mutations in the KIT or PDGFRA and the rest 15% cases which present without KIT or PDGFRA mutation are called wild type (WT) GISTs. Patients with neurofibromatosis type I (NF1) have higher risk of developing GISTs and all the cases belong to the WT GISTs. Compared with the somatic cases, NF1-associated GISTs are characterized with unique clinical manifestations and are not responding to Imatinib-the first line drug for GISTs. This study was designed to identify the central somatic mutations in NF1-associated GISTs by conducting whole exomes sequencing (WES). We sequenced the tumor and peripheral blood exomes of two patients who developed KIT/PDGFRA wild-type GISTs concurrent with NF1. Three novel somatic mutated genes (PRSS and FOLR3, and TAS2R43) were identified in GISTs but not NF1 tumors. And we further test the function of the mutated genes (PRSS3, FOLR3) in GIST cells and prove the oncogenic roles they play in NF-1 associated GIST. This is the first report, to our knowledge, that WES is applied to study the genomic profile of tumors and peripheral blood exomes in NF1 patients. And it is also the first time that PRSS3 and FOLR3 are revealed to be associated with the development of NF1-associated GISTs.