Department of Pathological Anatomy and Neuropathology, Timone Hospital, Public Assistance-Marseille Hospitals (APHM), Marseille, France.
Aix-Marseille University, Scientific Research National Center (CNRS), Institute of Neurophysiopathology, Marseille, France.
Neuro Oncol. 2019 Dec 17;21(12):1519-1528. doi: 10.1093/neuonc/noz124.
BACKGROUND: The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. METHODS: In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. RESULTS: CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas. CONCLUSIONS: Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.
背景：2016 年世界卫生组织（WHO）中枢神经系统肿瘤分类将异柠檬酸脱氢酶（IDH）突变型胶质瘤分为 2 大组，取决于是否存在 1p/19q 联合缺失。然而，分级系统保持不变，现在是否仍然可以将其应用于这一更新的分子分类存在争议。
方法：在法国国家 POLA 网络的 911 例高级别 IDH 突变型胶质瘤大队列中（包括 428 例无 1p/19q 联合缺失的 IDH 突变型胶质瘤和 483 例间变性少突胶质细胞瘤，IDH 突变和 1p/19q 联合缺失），我们研究了细胞周期蛋白依赖性激酶抑制剂 2A（CDKN2A）基因纯合缺失以及 WHO 分级标准（有丝分裂、微血管增殖和坏死）的预后价值。此外，我们在部分患者中还寻找了其他视网膜母细胞瘤途径基因改变（CDK4 扩增和 RB1 纯合缺失）。还在另外一组 40 例 IDH 突变型 II 级胶质瘤中搜索了 CDKN2A 纯合缺失。
结果：CDKN2A 纯合缺失与缺乏 1p/19q 联合缺失的 IDH 突变型胶质瘤（无进展生存期 P < 0.0001，总生存期 P = 0.004）以及 IDH 突变+1p/19q 联合缺失的间变性少突胶质细胞瘤相关（无进展生存期 P = 0.002，总生存期 P < 0.0001），在包括年龄、手术范围、辅助治疗、微血管增殖和坏死的单变量和多变量分析中。在这两组中，仅在缺乏 CDKN2A 纯合缺失的情况下，微血管增殖和/或坏死的存在仍具有预后价值。在 II 级胶质瘤中未记录到 CDKN2A 纯合缺失。
结论：我们的研究指出，CDKN2A 纯合缺失作为 IDH 突变型胶质瘤 2 大类别的不良预后因素具有重要意义，这些肿瘤的分级应进一步细化。
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