Hemmingsen Jonas Klejs, Enemark Marie Hairing, Sørensen Emma Frasez, Lauridsen Kristina Lystlund, Hamilton-Dutoit Stephen Jacques, Kridel Robert, Honoré Bent, Ludvigsen Maja
Department of Hematology, Aarhus University Hospital, 8200 Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Cancers (Basel). 2024 Sep 26;16(19):3278. doi: 10.3390/cancers16193278.
Follicular lymphoma (FL) is characterized by an indolent nature and generally favorable prognosis, yet poses a particular clinical challenge, since disease progression is observed in a notable subset of patients. Currently, it is not possible to anticipate which patients will be at risk of progression, highlighting the need for reliable predictive biomarkers that can be detected early in the disease. We applied tandem-mass-tag labelled nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) on 48 diagnostic formalin-fixed, paraffin-embedded tumor samples from patients with advanced-stage FL. Of these, 17 experienced subsequent progression (subsequently-progressing, sp-FL) while 31 did not (non-progressing, np-FL). We identified 99 proteins that were significantly differentially expressed between sp-FL samples and np-FL samples ( < 0.05; log-fold changes between 0.2 and -1.3). Based on this subset of proteins, we classified patients into high-risk and low-risk subgroups using unsupervised machine learning techniques. Pathway analyses of the identified proteins revealed aberrancies within the immune system and cellular energy metabolism. In addition, two proteins were selected for immunohistochemical evaluation, namely stimulator of interferon genes 1 (STING1) and isocitrate dehydrogenase 2 (IDH2). Notably, IDH2 retained significantly lower expression levels in sp-FL samples compared with np-FL samples ( = 0.034). Low IDH2 expression correlated with shorter progression-free survival (PFS, = 0.020). This study provides evidence for some of the biological mechanisms likely to be involved in FL progression and, importantly, identifies potential predictive biomarkers for improvement of risk stratification up-front at time of FL diagnosis.
滤泡性淋巴瘤（FL）具有惰性本质且通常预后良好，但仍带来了特殊的临床挑战，因为在相当一部分患者中会观察到疾病进展。目前，无法预测哪些患者有进展风险，这凸显了对可在疾病早期检测到的可靠预测生物标志物的需求。我们对48例晚期FL患者的诊断性福尔马林固定、石蜡包埋肿瘤样本应用了串联质量标签标记的纳米液相色谱串联质谱（nLC-MS/MS）。其中，17例随后出现进展（随后进展型，sp-FL），而31例未进展（未进展型，np-FL）。我们鉴定出99种在sp-FL样本和np-FL样本之间有显著差异表达的蛋白质（<0.05；对数变化倍数在0.2和-1.3之间）。基于这组蛋白质，我们使用无监督机器学习技术将患者分为高风险和低风险亚组。对鉴定出的蛋白质进行的通路分析揭示了免疫系统和细胞能量代谢中的异常。此外，选择了两种蛋白质进行免疫组织化学评估，即干扰素基因刺激因子1（STING1）和异柠檬酸脱氢酶2（IDH2）。值得注意的是，与np-FL样本相比，IDH2在sp-FL样本中的表达水平显著更低（=0.034）。低IDH2表达与无进展生存期缩短相关（PFS，=0.020）。本研究为FL进展可能涉及的一些生物学机制提供了证据，重要的是，在FL诊断时识别出潜在的预测生物标志物，以改善前期风险分层。
