title: Expression of DNA ligase IV is linked to poor prognosis and characterizes a subset of prostate cancers harboring TMPRSS2:ERG fusion and PTEN deletion.
abstract: DNA ligases are essential for the maintenance of genome integrity as they are indispensable for DNA replication, recombination and repair. The present study was undertaken to gain insights into the prevalence and clinical significance of ligase IV (LIG4) expression in prostate cancer. A total of 11,152 prostate cancer specimens were analyzed by immunohistochemistry for LIG4 expression. Results were compared to follow-up data, ERG status and deletions at PTEN, 3p13, 5q21 and 6q15. LIG4 expression was predominantly localized in the nucleus of the cells with increased intensities in malignant as compared to benign prostate epithelium. In prostate cancer, LIG4 expression was found in 91% of interpretable tumors, including 12% cancers with weak, 23% with moderate and 56% with strong LIG4 positivity. Strong LIG4 expression was tightly linked to advanced Gleason score (P<0.0001) and positive nodal involvement (P=0.03). There was a remarkable accumulation of strong LIG4 expression in tumors harboring TMPRSS2:ERG fusion and PTEN deletions (P<0.0001 each). High LIG4 expression was also tightly related to early biochemical recurrence when all tumors (P<0.0001) or the subsets of ERG-negative (P=0.0004) or ERG-positive prostate cancers (P=0.006) were analyzed. Multivariate analysis including parameters that are available before surgery demonstrated independent association with biochemical recurrence for advanced Gleason grade on biopsy, high preoperative PSA level, high clinical stage (P<0.0001 each) and for LIG4 immunostaining (P=0.03). Our study identifies LIG4 as a predictor of an increased risk for early PSA recurrence in prostate cancer. Moreover, the strong association with TMPRSS2:ERG fusion and PTEN deletions suggest important interactions between these pathways in prostate cancers.
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Grupp
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Roettger
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kluth
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hube-Magg
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lebok
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Tsourlakis
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Koop
authors.affiliation: Martini‑Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.affiliation: Martini‑Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Adam
authors.affiliation: Martini‑Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Haese
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Wittmer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
authors.affiliation: Martini‑Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Hartwig
authors.initials: H
authors.lastname: Huland
authors.affiliation: Martini‑Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Krech
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C000607893:LIG4 protein, human; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017430:Prostate-Specific Antigen; D011088:DNA Ligases; D000072481:DNA Ligase ATP