细胞周期依赖激酶抑制基因2A/B纯合缺失在组织病理2或3级脑胶质瘤中的临床意义

Clinical significance of cyclin-dependent kinase inhibitor 2A/B homozygous deletion in histopathological grade 2 or 3 gliomas

目的细胞周期蛋白依赖激酶抑制基因2A/B(CDKN2A/B)纯合缺失在较低级别胶质瘤(2或3级)中罕见,新版WHO分类将其定为恶性度最高4级。该研究旨在系统报道CDKN2A/B纯合缺失在较低级别胶质瘤中的临床特点、预后及相关功能通路。方法收集473例有CDKN2A/B纯合缺失、临床和预后信息的较低级别胶质瘤患者,对发生率、临床特点及预后统计分析;收集27例新鲜肿瘤标本(13例CDKN2A/B纯合缺失),通过Ki-67和CD31免疫组织化学分析细胞增殖和血管增生;在1116例胶质瘤RNA测序数据中对CDKN2A/B纯合缺失的相关功能和通路进行分析。结果CDKN2A/B纯合缺失在较低级别胶质瘤中发生率为7.2%(34/473),该缺失在年龄偏大、星形细胞瘤、3级、近全切及IDH野生型患者中发生率更高(均P<0.05)。在IDH突变型或野生型较低级别胶质瘤中,CDKN2A/B纯合缺失均与患者更短的总生存期和无进展生存期相关。缺失型标本Ki-67(P=0.045)和CD31(P=0.058)蛋白表达高于野生型。生物信息学显示CDKN2A/B纯合缺失激活DNA复制、修复和细胞周期等功能和通路。结论CDKN2A/B纯合缺失与较低级别胶质瘤患者差的预后和恶性表型有关,该类患者临床应积极治疗。

Objective Cyclin-dependent kinase inhibitor 2A/B(CDKN2A/B)homozygous deletion is rare in histopathological grade 2 or 3 lower-grade gliomas,and it is a grade IV malignancy based on the new WHO classification of tumors.This study aims to investigate the clinical features,prognosis,and related functional pathways in lower-grade gliomas with CDKN2A/B homozygous deletion.Methods Clinical data were collected from 473 patients with lower-grade gliomas with CDKN2A/B homozygous deletion information who had complete clinical and prognostic data,and a statistical analysis was performed for incidence rate,clinical features,and prognosis.A total of 27 fresh tumor specimens were collected,among which there were 13 specimens with CDKN2A/B homozygous deletion,and immunohistochemistry for Ki-67 and CD31 was used to analyze cell proliferation and angiogenesis.Functions and pathways associated with CDKN2A/B homozygous deletion were analyzed based on the RNA sequencing data of 1116 glioma cases.Results The incidence rate of CDKN2A/B homozygous deletion was 7.2%(34/473)in lower-grade gliomas,with a higher incidence rate in patients with older age,astrocytoma,grade 3 gliomas,near-total resection,or wild-type IDH(all P<0.05).CDKN2A/B homozygous deletion was associated with shorter overall survival and progression-free survival in IDH mutant patients or IDH wild-type patients.The protein expression levels of Ki-67 and CD31 in patients with CDKN2A/B homozygous deletion were significantly higher than those in wild-type patients(P=0.045 and 0.058).The bioinformatics analysis showed that CDKN2A/B homozygous deletion was associated with the functions and pathways such as activated DNA replication,repair,and cell cycle.Conclusions CDKN2A/B homozygous deletion is associated with the poor prognosis and malignant phenotype of patients with lower-grade gliomas,and these patients should receive active treatment in clinical practice.