title: Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: implications for the anti-tumor barrier concept and treatment.
abstract: The DNA damage response (DDR) machinery becomes commonly activated in response to oncogenes and during early stages of development of solid malignancies, with an exception of testicular germ cell tumors (TGCTs). The active DDR signaling evokes cell death or senescence but this anti-tumor barrier can be breached by defects in DDR factors, such as the ATM-Chk2-p53 pathway, thereby allowing tumor progression. The DDR barrier is strongly activated in brain tumors, particularly gliomas, due to oxidative damage and replication stress. Here, we took advantage of rare human primary intracranial germ cell tumors (PIGCTs), to address the roles of cell-intrinsic factors including cell of origin, versus local tissue environment, in the constitutive DDR activation in vivo. Immunohistochemical analysis of 7 biomarkers on a series of 21 PIGCTs (germinomas and other subtypes), 20 normal brain specimens and 20 glioblastomas, revealed the following: i) The overall DDR signaling (γH2AX) and activation of the ATM-Chk2-p53 pathway were very low among the PIGCTs, reminiscent of TGCTs, and contrasting sharply with strong DDR activation in glioblastomas; ii) Except for one case of embryonal carcinoma, there were no clear aberrations in the ATM-Chk2-p53 pathway components among the PIGCT cohort; iii) Subsets of PIGCTs showed unusual cytosolic localization of Chk2 and/or ATM. Collectively, these results show that PIGCTs mimic the DDR activation patterns of their gonadal germ cell tumor counterparts, rather than the brain tumors with which they share the tissue environment. Hence cell-intrinsic factors and cell of origin dictate the extent of DDR barrier activation and also the ensuing pressure to select for DDR defects. Our data provide conceptually important insights into the role of DNA damage checkpoints in intracranial tumorigenesis, with implications for the differential biological responses of diverse tumor types to endogenous stress as well as to genotoxic treatments such as ionizing radiation or chemotherapy.
authors: Danish Cancer Society Research Center, Copenhagen, Denmark. Electronic address: jib@cancer.dk.
authors: Jirina
authors: J
authors: Bartkova
authors: University Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark; Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark.
authors: Christina E
authors: CE
authors: Hoei-Hansen
authors: Danish Cancer Society Research Center, Copenhagen, Denmark; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors: Katerina
authors: K
authors: Krizova
authors: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors: Petra
authors: P
authors: Hamerlik
authors: University Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark.
authors: Niels E
authors: NE
authors: Skakkebæk
authors: University Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark. Electronic address: erm@rh.dk.
authors: Ewa
authors: E
authors: Rajpert-De Meyts
authors: Danish Cancer Society Research Center, Copenhagen, Denmark; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors: Jiri
authors: J
authors: Bartek
mesh_terms: D000293:Adolescent; D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D018303:Ganglioglioma / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D055815:Young Adult
chemical_list: D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human
keywords: ATM-Chk2-p53 pathway; DNA damage signaling; Gliomas; Intracranial germ cell tumors; Testicular germ cell neoplasms