title: High nuclear karyopherin α 2 expression is a strong and independent predictor of biochemical recurrence in prostate cancer patients treated by radical prostatectomy.
abstract: Increased levels of karyopherin α2 (KPNA2) expression have been described to be linked to poor prognosis in a variety of malignancies. This study was undertaken to evaluate the clinical impact of KPNA2 expression and its association with key genomic alterations in prostate cancers. A tissue microarray containing samples from 11 152 prostate cancers was analyzed for KPNA2 expression by immunohistochemistry. Results were compared with oncological follow-up data and genomic alterations such as TMPRSS2-ERG fusions and deletions of PTEN, 5q21, 6q15 or 3p13. KPNA2 expression was absent or weak in benign prostatic glands and was found to be in weak, moderate or strong intensities in 68.4% of 7964 interpretable prostate cancers. KPNA2 positivity was significantly linked to the presence of ERG rearrangement (P<0.0001). In ERG-negative and -positive prostate cancers, KPNA2 immunostaining was significantly associated with advanced pathological tumor stage (pT3b/pT4), high Gleason grade and early biochemical recurrence (P<0.0001 each). Multivariate analysis including all established prognostic criteria available after surgery revealed that the prognostic role of KPNA2 (P=0.001) was independent of high Gleason grade, advanced pathological tumor stage, high preoperative prostate-specific antigen level and positive surgical margin status (P<0.0001 each). The comparison of KPNA2 expression with deletions of PTEN, 5q21, 6q15 and 3p13 in ERG-positive and -negative cancers revealed a strong link to PTEN deletions in both subgroups (P<0.0001). In conclusion, the strong independent prognostic impact of KPNA2 expression raises the possibility that measurement of KPNA2 expression alone or in combination with other molecular parameters might possibly result in clinically useful information. The data also emphasize a critical role of the functionality of the nuclear import machinery for prostate cancer biology.
authors.affiliation: 1] General, Visceral and Thoracic Surgery Department and Clinic, Hamburg, Germany [2] Institute of Pathology, Hamburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Grupp
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Habermann
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Sirma
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hube-Magg
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Prien
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Lia
authors.initials: L
authors.lastname: Burkhardt
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Jedrzejewska
authors.affiliation: Martini-Clinic, Prostate Cancer Center, Hamburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Salomon
authors.affiliation: Martini-Clinic, Prostate Cancer Center, Hamburg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Heinzer
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kluth
authors.affiliation: General, Visceral and Thoracic Surgery Department and Clinic, Hamburg, Germany.
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.affiliation: 1] Martini-Clinic, Prostate Cancer Center, Hamburg, Germany [2] Department of Urology, Section for translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.affiliation: Institute of Pathology, Hamburg, Germany.
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Tsourlakis
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002467:Cell Nucleus / Q000737:chemistry*; D002872:Chromosome Deletion; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D007610:Kallikreins / Q000032:analysis*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000032:analysis*; D011468:Prostatectomy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000097:blood / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D013997:Time Factors; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG; D016896:Treatment Outcome; D028901:alpha Karyopherins / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; C072312:ERG protein, human; C490630:KPNA2 protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D028901:alpha Karyopherins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen