KIT A502_Y503 重复突变可作为中国 GIST 患者新抗原肽的潜在通用靶点。

KIT A502_Y503 duplication mutation serves as a potential and universal target for neoantigen peptide in Chinese GIST patients.

机构信息

Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School and Clinical Cancer Institute of Nanjing University, Nanjing, China.

出版信息

J Gastroenterol Hepatol. 2023 Jul;38(7):1123-1130. doi: 10.1111/jgh.16165. Epub 2023 Mar 16.

DOI:10.1111/jgh.16165

PMID:36879550

Abstract

BACKGROUND AND AIM

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor with high prevalence of KIT and PDGFRA mutations. Few effective treatments can be exploited in imatinib or sunitinib resistant cases. While in immunotherapy, application of the highly individualized cancer neoantigen vaccines is hampered due to high economic and time cost. In this study we identified the most frequent mutation in Chinese GIST patients and predicted candidate neopeptide by next generation sequencing (NGS).

METHODS

Tumor tissues and matched blood samples of 116 Chinese GIST patients were collected. Genomic profile was detected through NGS, and 450 cancer genes were deeply sequenced. KIT mutations were identified, and long peptides containing the mutation were queried in NetMHCpan 4.0 tools to predict MHC class I binding of mutant peptides.

RESULTS

The most frequent mutated genes in detected GIST patients were KIT (81.9%, 95/116), CDKN2A (18.97%, 22/116), and CDKN2B (15.52%, 18/116) in this cohort. The most common mutation of KIT was A502_Y503 duplication (15.93%, 18/113) in exon 9. Among the 116 cases, 103 were HLA I genotyped, and 101 were HLA II genotyped. In total, 16 samples with the mutation of KIT p.A502_Y503dup were identified to produce neoantigens with qualified HLA affinity.

CONCLUSIONS

KIT hotspot mutation (p.A502_Y503dup) has the highest incidence, which may further eliminate the need for whole genome sequencing and patient-specific neoantigen prediction and synthesis. Therefore, for those carrying such mutation, accounting for around 16% of Chinese GIST patients and are usually less sensitive to imatinib, effective immunotherapies are in prospect.

摘要

背景与目的

胃肠道间质瘤（GIST）是最常见的间叶性肿瘤，其 KIT 和 PDGFRA 突变率较高。对于伊马替尼或舒尼替尼耐药的病例，几乎没有有效的治疗方法。而在免疫治疗中，由于高经济和时间成本，高度个体化的癌症新抗原疫苗的应用受到限制。在本研究中，我们通过下一代测序（NGS）鉴定了中国 GIST 患者最常见的突变，并预测了候选新肽。

方法

收集 116 例中国 GIST 患者的肿瘤组织和配对血样。通过 NGS 检测基因组谱，对 450 个肿瘤基因进行深度测序。鉴定 KIT 突变，并在 NetMHCpan 4.0 工具中查询包含突变的长肽，以预测突变肽与 MHC Ⅰ类分子的结合。

结果

在本研究队列中，检测到的 GIST 患者最常见的突变基因是 KIT（81.9%，95/116）、CDKN2A（18.97%，22/116）和 CDKN2B（15.52%，18/116）。KIT 外显子 9 中最常见的突变是 A502_Y503 重复（15.93%，18/113）。在 116 例患者中，有 103 例进行了 HLA I 基因分型，101 例进行了 HLA II 基因分型。总共鉴定出 16 例 KIT p.A502_Y503dup 突变的样本，这些样本产生具有合格 HLA 亲和力的新抗原。