HG-05: DIFFERENTIAL EXPRESSION OF PARP1/2 AS A BIOMARKER OF DIPG MALIGNANT PROGRESSION: RELATIONSHIP TO TGF-β/BMP SIGNALING AND EZH2 GLOBAL METHYLATION

Diffuse intrinsic pontine gliomas (DIPG) which occur in the brain stem are the most malignant inoperable and hard to treat brain tumors in children. Many reports indicate DIPG as being unique in terms of the molecular process that drives their malignancy. Recently, Poly (ADP-ribose) polymerase 1 & 2 (PARP1/2) have gained much attention as potential promising therapeutic targets for the treatment of solid tumors including DIPG. In this study, we defined molecular landscape of DIPG tumor samples by using a large public retrospective gene expression data set (n = 53) and performed detailed bio-informatics analysis to generate hypotheses regarding potential mechanisms associated with PARP expression. Different associations between PARP and TGF-β/BMP, EZH2 signaling pathway genes were observed (low vs high). We found a negative co-relation between PARP expression and TGBRII, BMP2 and BMP2K genes, with much stronger correlation in patients with H3F3A mutation (present in 65-75% of tumors) suggesting negative role of PARP on TGF-β/BMP signaling. We noticed significant positive correlation of PARP with EZH2 and UHRF1BP1 genes known to regulate global methylation and their increased expression is recognized to inhibit genes responsible for suppressing tumor development. Further patients with high PARP expression along with high EZH2 and low BMP signaling were correlated with poor prognosis to survival. In conclusion, these results reveal potential biological role of PARP in regulating TGF-β/BMP signaling and global methylation driving DIPG tumorigenesis. Moreover, these findings delineate pathways of susceptibility that could be disrupted to confer strong sensitivity to PARP inhibitors.