Stecko Hunter, Iyer Sidharth, Tsilimigras Diamantis, Pawlik Timothy M
Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, Ohio, USA.
The Ohio State University College of Medicine, Columbus, Ohio, USA.
Oncology. 2025;103(4):327-340. doi: 10.1159/000541454. Epub 2024 Sep 21.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract, the treatment of which represents a significant breakthrough in targeted cancer therapy. Given its overall rare nature, genomic differences and clinical implications between demographic groups have not been previously investigated.
Anonymized demographic, clinical, and genomic data from 1,559 GIST patients in the American Association for Cancer Research Project GENIE database were analyzed using cBioPortal and custom Python scripts. Data on patient demographics, genomic alterations, and co-occurrence genetic alerations were collected and classified according to clinical implications using the OncoKB database. χ2 tests for differences in genomic alterations were used across various demographic factors and mutual exclusivity analysis was employed to identify co-mutation patterns.
Male patients demonstrated higher incidence of PDGFRA mutation (14.56% vs. 8.05%; p < 0.001), while female patients had higher likelihood of NF1 mutations (7.46% vs. 3.23%; p = 0.001). Asian patients had higher alteration rates at KIT (85.59%; p = 0.002). Co-occurrence analysis revealed KIT alterations frequently co-occurred with CDKN2A (q < 0.001), MTAP (q = 0.045), and PTEN (q = 0.056), while there was mutual exclusivity with PDGFRA (q < 0.001), NF1 (q < 0.001), and BRAF (q = 0.015). CDKN2A alterations co-occurred with MTAP (q < 0.001) and PIK3CA (q = 0.015), while being mutually exclusive with TP53 (q = 0.002) and NF1 (q = 0.007). Trends were similar among patients who had received no prior medical treatment. Imatinib-resistant mutations were more common among male patients (25.6% vs. 18.9%; p = 0.0056) and individuals under 55 (27.3% vs. 20.9%; p = 0.0228). Among patients with imatinib-resistant mutations, 77.78% had sunitinib resistance, while 70.25% maintained sensitivity to ripretinib.
Sex and race/ethnic differences in genomic alterations, as well as co-mutations, were prevalent among patients with GIST. Variations in mutational profiles highlight the importance of distinct genetic drivers that may be targeted to treat different patient populations.
胃肠道间质瘤（GISTs）是胃肠道最常见的间叶性肿瘤，其治疗是靶向癌症治疗的一项重大突破。鉴于其总体罕见性，此前尚未研究不同人群之间的基因组差异及其临床意义。
使用cBioPortal和自定义Python脚本分析了美国癌症研究协会项目GENIE数据库中1559例GIST患者的匿名人口统计学、临床和基因组数据。收集了患者人口统计学、基因组改变和共现基因改变的数据，并使用OncoKB数据库根据临床意义进行分类。对各种人口统计学因素进行基因组改变差异的χ2检验，并采用互斥性分析来确定共突变模式。
男性患者中血小板衍生生长因子受体A（PDGFRA）突变的发生率更高（14.56%对8.05%；p<0.001），而女性患者中神经纤维瘤病1型（NF1）突变的可能性更高（7.46%对3.23%；p = 0.001）。亚洲患者中KIT的改变率更高（85.59%；p = 0.002）。共现分析显示，KIT改变常与细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）（q<0.001）、甲基硫代腺苷磷酸化酶（MTAP）（q = 0.045）和磷酸酶及张力蛋白同源物（PTEN）（q = 0.056）共同出现，而与PDGFRA（q<0.001）、NF1（q<0.001）和B-Raf原癌基因丝氨酸/苏氨酸激酶（BRAF）（q = 0.015）相互排斥。CDKN2A改变与MTAP（q<0.001）和磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA）（q = 0.015）共同出现，而与肿瘤蛋白p53（TP53）（q = 0.002）和NF1（q = 0.007）相互排斥。在未接受过先前治疗的患者中也观察到了类似趋势。伊马替尼耐药突变在男性患者（25.6%对18.9%；p = 0.0056）和55岁以下个体（27.3%对20.9%；p = 0.0228）中更为常见。在具有伊马替尼耐药突变的患者中，77.78%对舒尼替尼耐药，而70.25%对瑞派替尼仍敏感。
GIST患者中基因组改变以及共突变存在性别和种族/民族差异。突变谱的差异凸显了针对不同患者群体进行靶向治疗的不同遗传驱动因素的重要性。
