title: DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer.
abstract: The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.
authors.affiliation: Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kurfurstova
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden. Electronic address: jib@cancer.dk.
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Vrtel
authors.affiliation: Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Mickova
authors.affiliation: Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Burdova
authors.affiliation: Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Dusana
authors.initials: D
authors.lastname: Majera
authors.affiliation: Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Mistrik
authors.affiliation: Department of Urology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Kral
authors.affiliation: Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria.
authors.forename: Frederic R
authors.initials: FR
authors.lastname: Santer
authors.affiliation: Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. Electronic address: jan.bouchal@upol.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Bouchal
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. Electronic address: jb@cancer.dk.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004249:DNA Damage; D004260:DNA Repair; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000032:analysis / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000235:genetics; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: DNA damage response barrier; NQO1 and oxidative stress; PARP inhibitor biomarkers; Prostate tumorigenesis; TMPRSS2-ERG; p53 and NKX3.1 tumour suppressors