Prognostic implications of the DNA damage response pathway in glioblastoma

• Published in: Oncology reports Vol. 26; no. 2; pp. 423 - 430
• Main Authors: HO JUN SEOL, HAE YONG YOO, JONG HYUN KIM, LEE, Jung-Ii, NAM, Do-Hyun, JUYOUN JIN, KYEUNG MIN JOO, KONG, Doo-Sik, SU JIN YOON, HEEK YOUNG YANG, WONYOUNG KANG, LIM, Do-Hoon, PARK, Kwan
• Format: Journal Article
• Language: English
• Published: Athens Spandidos 01.08.2011
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Cell Line, Tumor; Child; DNA Damage; Female; Glioblastoma - genetics; Glioblastoma - metabolism; Humans; Immunohistochemistry; Male; Medical sciences; Middle Aged; Neurology; Prognosis; Signal Transduction; Tumors; Tumors of the nervous system. Phacomatoses; Young Adult; Malignant glioma; Nervous system diseases; Cancerology; Prognosis; DNA damage response; Central nervous system disease; Glioblastoma; ATM; Malignant tumor; Cancer; Tumor suppressor gene
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2011.1325

Genomic instability and resistance to genotoxic therapies for glioblastoma (GBM) suggest aberrant DNA damage response (DDR), since DDR maintains the genomic integrity against genotoxic insults including anti-tumor therapies. To elucidate the biological and clinical meaning of DDR in GBM, we retrospectively investigated the immunohistochemical expression of DDR proteins (ATM, Chk1, Chk2, TopBP1, Rad17, p53, Nbs1, MDC1, γH2AX and RPA1) in 69 GBM surgical samples and their relation with GBM patient survival. Remarkably, higher expression of ATM revealed significantly longer overall survival (OS) and progression-free survival (PFS) (p<0.05). Upon multivariate analysis, expression level of ATM was an independent factor for longer OS (p=0.020) and longer PFS (p=0.019). Since ATM induces cell cycle arrest or apoptosis through cell cycle regulators in response to genotoxic insults, these results indicate that aberrant DDR signaling through ATM in GBM may be associated with resistance to genotoxic anti-tumor therapeutics. Conclusively, we emphasize that the identification of DDR machinery, which can be involved in unstable genomic status or genotoxic therapies in GBM, is very important to predict patient outcome.