Kleijn Tony G, Ameline Baptiste, Bleckman Roos F, Kooistra Wierd, van den Broek Evert, Diercks Gilles F H, van Hemel Bettien M, Timmer Bert, Timens Wim, Kats-Ugurlu Gursah, van Kempen Léon C, van Etten Boudewijn, Schuuring Ed, Suurmeijer Albert J H, de Haan Jacco J, Baumhoer Daniel, Reyners Anna K L, Cleven Arjen H G
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Bone Tumor Reference Center at the Institute for Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
Genes Chromosomes Cancer. 2025 Mar;64(3):e70046. doi: 10.1002/gcc.70046.
Gastrointestinal stromal tumors (GISTs) span a broad clinical spectrum, from indolent neoplasms to life-threatening metastatic tumors. A persistent limitation of current risk stratification systems is that a subset of GISTs is graded as low-risk but nevertheless metastasizes. Therefore, new predictive factors that improve risk stratification are needed. In this exploratory study, we investigated the potential of genome-wide DNA methylation profiling and copy number variation (CNV) analysis as additional prognostic tools for GISTs. We collected a cohort of 28 patients with GIST diagnosed between 2001 and 2022, with available follow-up and molecular data. This included 15 patients without progressive disease (seven low-risk and eight moderate- to high-risk GISTs) and 13 with progressive disease. Among those with progression, eight experienced recurrence or metastasis post-surgery (one low-risk, seven high-risk GISTs), while five had metastatic disease at initial diagnosis. Risk stratification was determined according to Miettinen's criteria. Genome-wide DNA methylation data and CNV plots were generated from imatinib-naïve primary GISTs using the Illumina Infinium MethylationEPIC BeadChip array. Unsupervised cluster analysis revealed distinct DNA methylation patterns predominantly associated with anatomical location and genotype. Differential DNA methylation analysis comparing primary gastric GISTs associated with and without progressive disease showed 8 differentially methylated regions spanning the coding and promoter areas of 6 genes. CNV analysis demonstrated that GISTs associated with progressive disease had the most CNVs, whereas low-risk, non-progressive GISTs had the fewest. Despite the limited sample size, this exploratory study indicates that genome-wide DNA methylation profiling and CNV analysis could enhance GIST risk stratification.
胃肠道间质瘤（GISTs）临床谱广泛，从惰性肿瘤到危及生命的转移性肿瘤。当前风险分层系统一直存在的局限性在于，一部分GISTs被分级为低风险但仍会发生转移。因此，需要新的改善风险分层的预测因素。在这项探索性研究中，我们调查了全基因组DNA甲基化谱分析和拷贝数变异（CNV）分析作为GISTs额外预后工具的潜力。我们收集了一组28例在2001年至2022年期间诊断为GIST的患者，他们有可用的随访和分子数据。其中包括15例无疾病进展的患者（7例低风险和8例中高风险GISTs）以及13例有疾病进展的患者。在有疾病进展的患者中，8例术后出现复发或转移（1例低风险、7例高风险GISTs），而5例在初诊时即有转移性疾病。根据米耶蒂宁标准确定风险分层。使用Illumina Infinium MethylationEPIC BeadChip芯片从未接受伊马替尼治疗的原发性GISTs中生成全基因组DNA甲基化数据和CNV图。无监督聚类分析揭示了主要与解剖位置和基因型相关的不同DNA甲基化模式。比较有和无疾病进展相关的原发性胃GISTs的差异DNA甲基化分析显示，有8个差异甲基化区域跨越6个基因的编码区和启动子区。CNV分析表明，与疾病进展相关的GISTs的CNV最多，而低风险、无疾病进展的GISTs的CNV最少。尽管样本量有限，但这项探索性研究表明，全基因组DNA甲基化谱分析和CNV分析可增强GIST风险分层。
