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

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:

• gastrointestinal stromal tumor
• NF1
• KIT
• deep sequencing

Acknowledgment

We want to give our thanks to Omar Abdihamid who check the words, grammar and English expression in the manuscript and attached legends.

Ethics Statement

The retrospective study was approved by the Institutional Review Board (IRB) of Xiangya Hospital of Central South University, and informed consent of patients from Xiangya Hospital was waived (IRB No. 202,009,686). The signed informed consent was obtained from the patients of the Gene+ dataset, and not required for the patients of MSKCC dataset which belongs to the cBioPortal database since it was publicly available. The study was directed in accordance with the recommendations delineated in the World Medical Association Declaration of Helsinki. All personal data within this study were remained confidential and not for commercial use.

Disclosure

Qiongzhi He is an employee of Geneplus-Beijing Institute. The authors declare that they have no other potential conflicts of interest for this work.