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

Jinchun Wu; Haiyan Zhou; Xiaoping Yi; Qiongzhi He; Tianxiang Lei; Fengbo Tan; Heli Liu; Bin Li

doi:10.2147/CMAR.S280174

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

Cancer Manag Res. 2021 Jan 12:13:297-306. doi: 10.2147/CMAR.S280174. eCollection 2021.

Authors

Jinchun Wu¹, Haiyan Zhou², Xiaoping Yi³, Qiongzhi He⁴, Tianxiang Lei⁵, Fengbo Tan⁵, Heli Liu⁵, Bin Li¹

Affiliations

¹ Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China.
² Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China.
³ Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China.
⁴ Geneplus-Beijing Institute, Beijing, People's Republic of China.
⁵ Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China.

Abstract

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: KIT; NF1; deep sequencing; gastrointestinal stromal tumor.

Grants and funding

This work was granted by the National Natural Science Foundation of China (81200366, 81572281, 81702278, 81974367) and Province Natural Science Foundation of Hunan (No. 14JJ6004) and the Key Subject Education Department of Hunan ([2012]594) and Scientific Research Project of Hunan Provincial Department of Education (No. 18K001).