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< 0.05). No mutation hotspot existed in mNF1 . Most of mKIT  centered within exon 11 (7/12, 58%) and others including exon 17 (3/12, 25%), exon 9(1/12, 8%), exon 13 (1/12, 8%) and exon 21 (1/12, 8%). No differences in age, gender, and location were detected between NF1 -related GISTs with mKIT  and those without mKIT . Three GIST cases of type I neurofibromatosis, skin neurofibromas and micro-GISTs (≤ 1 cm) were devoid of mKIT , but all the mini-GISTs (1∼ 2 cm) and clinic GIST lesions (> 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.
Keywords: gastrointestinal stromal tumor, NF1 , KIT , deep sequencing