title: Aberrations of the Chk2 tumour suppressor in advanced urinary bladder cancer.
abstract: Checkpoint kinase 2 (Chk2) is a tumour suppressor and signal transducer in genome integrity checkpoints that coordinate cell-cycle progression with DNA repair or cell death in response to DNA damage. Defects of Chk2 occur in subsets of diverse sporadic malignancies and predispose to several types of hereditary carcinomas. However, the status of Chk2 in tumours of the urinary bladder remains unknown. Here, we report that among 58 advanced (grade T2-T4) human bladder carcinomas, immunohistochemical analysis revealed tumour-specific reduction or lack of Chk2 protein in 6 (10.3%) cases. Genetic analysis of the latter subset showed that a Chk2-negative carcinoma #668 harboured a truncating mutation 1100delC, in one Chk2 allele and loss of the corresponding second allele. The 1100delC mutation was also found in the germ line of this patient. Sequencing of TP53 in tumour #668 identified two missense mutations. Furthermore, the vast majority of the tumours showed 'unscheduled' activatory phosphorylation on Thr68 of Chk2 in the absence of any DNA-damaging treatment. Our results indicate that the otherwise dormant DNA damage signal transducer Chk2 is aberrantly and constitutively activated in invasive urinary bladder carcinomas, and that such likely proapoptotic checkpoint signalling can be disabled by inactivation of Chk2 and/or p53 tumour suppressors in subsets of these tumours.
authors.affiliation: Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.forename: Kirsten
authors.initials: K
authors.lastname: Grønbaek
authors.forename: Karen
authors.initials: K
authors.lastname: Koed
authors.forename: Hanne
authors.initials: H
authors.lastname: Primdahl
authors.forename: Klaus
authors.initials: K
authors.lastname: Møller
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D064447:Checkpoint Kinase 2; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases