Targeted Deep Sequencing Reveals Unrecognized KIT Mutation Coexistent with NF1 Deficiency in GISTs

Purpose NF1-deficient GISTs account for about 1% of gastrointestinal stromal tumors (GISTs) and are usually considered as a subtype of KIT/PDGFRA wild-type GISTs that have no detectable KIT and PDGFRA mutations. Some KIT/PDGFRA wild-type GISTs actually have cryptic KIT mutations (mKIT). So we investigate whether concurrent mKIT existed in NF1-associated GISTs. Patients and methods Three independent cohorts were retrospectively analyzed. KIT/PDGFRA wild-type GISTs in Xiangya Hospital between May 2017 and Oct 2019 were investigated by next-generation sequencing (NGS) approach targeted 1021 cancer-related genes regions. GISTs cases in Gene+ dataset from May 2017 to May 2020 were collected from the platform of this company. The genotypes of GISTs in MSKCC cohort were downloaded from cBioPortal. Results A total of 290 cases including 23 KIT/PDGFRA wild-type GISTs in Xiangya Hospital, 136 GISTs in Gene+ database, and 131 GISTs in MSKCC were enrolled. Twenty-six cases have NF1 mutations (mNF1), and 48% (12/26) of NF1-mutated GISTs have concurrent mKIT. Compared with MSKCC (2/10, 20%), a higher ratio of mKIT in NF1-associated GISTs was detected in Xiangya Hospital (3/5, 60%) and Gene+ (7/11, 64%) (p 2 cm) in two cases harbored mKIT. Conclusion mKIT was not unusual in NF1-associated GISTs, especially in Chinese populations. The gain-of-function mKIT possibly facilitated the progression of NF1-deficient lesions to clinic GISTs, however, the underlying mechanism warrants further studies.