Tomczak Katarzyna, Patel Manishkumar S, Bhalla Angela D, Peterson Christine B, Landers Sharon M, Callahan S Carson, Zhang Di, Wong Justin, Landry Jace P, Lazar Alexander J, Livingston J Andrew, Guadagnolo B Ashleigh, Lyu Heather G, Lillemoe Heather, Roland Christina L, Keung Emily Z, Scally Christopher P, Hunt Kelly K, McCutcheon Ian E, Slopis John M, Gu Jian, Scheet Paul, Wang Liang, Rai Kunal, Torres Keila E
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Mol Carcinog. 2025 Jan;64(1):44-56. doi: 10.1002/mc.23825. Epub 2024 Nov 26.
Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST-specific biomarkers for screening patients with NF1. Genome-wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1-MPNST cell lines was performed to identify and validate candidate MPNST-specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST-specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD-seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature-selection criteria and predictive modeling, we identified 73 candidate MPNST-specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2-fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be investigated further as biomarkers in clinical settings for early MPNST detection in patients with NF1.
恶性外周神经鞘膜瘤（MPNST）的发生发展具有DNA甲基化格局改变的特征，这为开发用于筛查1型神经纤维瘤病（NF1）患者的MPNST特异性生物标志物提供了一个有前景的领域。对13例MPNST患者（29份肿瘤及相邻神经纤维瘤组织样本）队列以及NF1-MPNST细胞系进行全基因组DNA甲基化分析，以识别和验证候选MPNST特异性CpG位点（CpGs）。构建逻辑回归预测模型，以选择与相邻神经纤维瘤和正常组织不同的MPNST特异性CpGs。为了检测MPNST患者血浆中是否也能检测到所选CpGs的高甲基化，应用cfMBD-seq分析MPNST患者和NF1患者血液中的cfDNA甲基化组。基于严格的特征选择标准和预测模型，我们鉴定出73个候选MPNST特异性CpGs（67个具有独特的CpG岛位置），它们能够可靠地将MPNST与神经纤维瘤区分开来。对5种候选生物标志物的验证证实，在组织中成功检测到MPNST（敏感性：>88%，特异性：>91%）。在血浆样本中，67个选定基因组区域中的63个在MPNST患者中的甲基化水平比NF1患者高1.2倍以上。此外，我们鉴定出15个CpG岛，它们能持续将确诊为MPNST的患者血浆与未诊断为恶性转化的NF1个体血浆区分开来（错误发现率<0.1）。我们的研究结果证实了恶性转化过程中存在独特的高甲基化模式。本研究强调了这些标志物在临床环境中作为早期检测NF1患者MPNST的生物标志物进一步研究的潜力。
