Murnyák Balázs, Kouhsari Mahan C, Hershkovitch Rotem, Kálmán Bernadette, Marko-Varga György, Klekner Álmos, Hortobágyi Tibor
Division of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Institute of Diagnostics, Faculty of the Health Sciences, University of Pecs, Pecs, Hungary.
Oncotarget. 2017 Jul 11;8(28):46348-46362. doi: 10.18632/oncotarget.18013.
Overexpression of PARP1 exists in various cancers, including glioblastoma (GBM). Although PARP1 inhibition is a promising therapeutic target, no comprehensive study has addressed PARP1's expression characteristics and prognostic role regarding molecular heterogeneity in astrocytomas including GBM. Our aim was to evaluate PARP1's associations with survival, WHO grade, lineage specific markers, and GBM transcriptomic subtypes. We collected genomic and clinical data from the latest glioma datasets of The Cancer Genome Atlas and performed PARP1, ATRX, IDH1, and p53 immunohistochemistry on GBM tissue samples. We demonstrated that PARP1 gain and increased mRNA expression are characteristics of high-grade astrocytomas, particularly of Proneural and Classical GBM subtypes. Additionally, higher PARP1 levels exhibited an inverse correlation with patient survival (p<0.005) in the Classical subgroup. ATRX (p=0.006), and TP53 (p=0.015) mutations were associated with increased PARP1 expression and PARP1 protein level correlated with ATRX loss and p53 overexpression. Furthermore, higher PARP1 expression together with wildtype TP53 indicated shorter survival (p=0.039). Therefore, due to subtype specificity, PARP1 expression level and TP53 mutation status are reliable marker candidates to distinguish Proneural and Classical subtypes, with prognostic and therapeutic implications in GBM.
PARP1的过表达存在于包括胶质母细胞瘤（GBM）在内的多种癌症中。尽管PARP1抑制是一个有前景的治疗靶点，但尚无全面研究探讨PARP1在包括GBM在内的星形细胞瘤分子异质性方面的表达特征和预后作用。我们的目的是评估PARP1与生存、世界卫生组织（WHO）分级、谱系特异性标志物以及GBM转录组亚型之间的关联。我们从癌症基因组图谱的最新胶质瘤数据集中收集了基因组和临床数据，并对GBM组织样本进行了PARP1、ATRX、IDH1和p53免疫组化。我们证明，PARP1的增加和mRNA表达的升高是高级别星形细胞瘤的特征，尤其是神经干细胞型和经典型GBM亚型。此外，在经典亚组中，较高的PARP1水平与患者生存呈负相关（p<0.005）。ATRX（p=0.006）和TP53（p=0.015）突变与PARP1表达增加相关，PARP1蛋白水平与ATRX缺失和p53过表达相关。此外，较高的PARP1表达与野生型TP53共同表明生存时间较短（p=0.039）。因此，由于亚型特异性，PARP1表达水平和TP53突变状态是区分神经干细胞型和经典型亚型的可靠候选标志物，对GBM具有预后和治疗意义。
