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

Purpose: -deficient GISTs account for about 1% of gastrointestinal stromal tumors (GISTs) and are usually considered as a subtype of wild-type GISTs that have no detectable and mutations. Some wild-type GISTs actually have cryptic mutations (). So we investigate whether concurrent existed in -associated GISTs.

Patients And Methods: Three independent cohorts were retrospectively analyzed. 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 wild-type GISTs in Xiangya Hospital, 136 GISTs in Gene+ database, and 131 GISTs in MSKCC were enrolled. Twenty-six cases have mutations (), and 48% (12/26) of -mutated GISTs have concurrent . Compared with MSKCC (2/10, 20%), a higher ratio of in -associated GISTs was detected in Xiangya Hospital (3/5, 60%) and Gene+ (7/11, 64%) (p<0.05). No mutation hotspot existed in . Most of 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 -related GISTs with and those without . Three GIST cases of type I neurofibromatosis, skin neurofibromas and micro-GISTs (≤1 cm) were devoid of , but all the mini-GISTs (1~2 cm) and clinic GIST lesions (>2 cm) in two cases harbored .

Conclusion: was not unusual in -associated GISTs, especially in Chinese populations. The gain-of-function possibly facilitated the progression of -deficient lesions to clinic GISTs, however, the underlying mechanism warrants further studies.