Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
PLoS One. 2023 May 16;18(5):e0285732. doi: 10.1371/journal.pone.0285732. eCollection 2023.
Accumulating evidence shows that mesenchymal transition of glioblastomas is associated with a more aggressive course of disease and therapy resistance. In WHO2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition of the tumor phenotype over time, has not been studied. Most efforts to correlate proneural, classical or mesenchymal phenotype with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype predicted survival and tumor recurrence in a clinical cohort of dLGGs, re-classified according to the 2021 WHO criteria.
Using a TMA-based approach with five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2), we investigated 183 primary and 49 recurrent tumors derived from patients with previously diagnosed dLGG. Of the 49 relapses, nine tumors recurred a second time, and one a third time.
In total, 71.0% of all tumors could be subtyped. Proneural was most dominant in IDH-mut tumors (78.5%), mesenchymal more common among IDH-wt tumors (63.6%). There was a significant difference in survival between classical, proneural and mesenchymal phenotypes in the total cohort (p<0.001), but not after molecular stratification (IDH-mut: p = 0.220, IDH-wt: p = 0.623). Upon recurrence, proneural was retained in 66.7% of the proneural IDH-mut dLGGs (n = 21), whereas IDH-wt tumors (n = 10) mainly retained or gained mesenchymal phenotype. No significant difference in survival was found between IDH-mut gliomas remaining proneural and those shifting to mesenchymal phenotype (p = 0.347).
Subtyping into classical, proneural and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but protein signatures did not correlate with patient survival in our WHO2021-stratified cohort. At recurrence, IDH-mut tumors mainly retained proneural, while IDH-wt tumors mostly retained or gained mesenchymal signatures. This phenotypic shift, associated with increased aggressiveness in glioblastoma, did not affect survival. Group sizes were, however, too small to draw any firm conclusions.
越来越多的证据表明胶质母细胞瘤的间质转化与疾病更具侵袭性和治疗耐药性有关。在 2021 年世界卫生组织（WHO）定义的成人型低级别弥漫性胶质瘤（dLGG）中，肿瘤表型随时间的转变尚未得到研究。大多数将前神经型、经典型或间质型表型与 dLGG 预后相关的努力都是在 2021 年 WHO 分类之前进行的。在这里，我们着手研究在根据 2021 年 WHO 标准重新分类的 dLGG 临床队列中，表型是否可以预测生存和肿瘤复发。
我们使用基于 TMA 的方法和五种免疫组织化学标志物（EGFR、p53、MERTK、CD44 和 OLIG2），对 183 例原发性和 49 例复发性来源于先前诊断为 dLGG 患者的肿瘤进行了研究。在 49 例复发肿瘤中，有 9 例肿瘤第二次复发，1 例第三次复发。
总共，71.0%的肿瘤可以进行亚型分类。IDH 突变型肿瘤中前神经型最为常见（78.5%），IDH 野生型肿瘤中间质型更为常见（63.6%）。在总队列中，经典型、前神经型和间质型表型在生存方面存在显著差异（p<0.001），但在分子分层后则无差异（IDH 突变型：p=0.220，IDH 野生型：p=0.623）。在复发时，IDH 突变型 dLGG 中的 66.7%（n=21）保留前神经型，而 IDH 野生型肿瘤（n=10）主要保留或获得间质型表型。IDH 突变型胶质瘤中保留前神经型和转变为间质型的肿瘤之间的生存无显著差异（p=0.347）。
通过五种免疫组织化学标志物将肿瘤分为经典型、前神经型和间质型，对于大多数肿瘤是可行的，但在我们的 2021 年 WHO 分层队列中，蛋白质特征与患者生存无关。在复发时，IDH 突变型肿瘤主要保留前神经型，而 IDH 野生型肿瘤主要保留或获得间质型特征。这种与胶质母细胞瘤侵袭性增加相关的表型转变并没有影响生存。然而，由于组间样本量太小，无法得出任何明确的结论。
