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2 Expression Is a Strong and Independent Predictor Of Modern Pathology (2014) 27, 96–106 96 & 2014 USCAP, Inc All rights reserved 0893-3952/14 $32.00 High nuclear karyopherin a 2 expression is a strong and independent predictor of biochemical recurrence in prostate cancer patients treated by radical prostatectomy Katharina Grupp1,2,5, Mareike Habermann2,5,Hu¨ seyin Sirma2, Ronald Simon2, Stefan Steurer2, Claudia Hube-Magg2, Kristina Prien2, Lia Burkhardt2, Karolina Jedrzejewska2, Georg Salomon3, Hans Heinzer3, Waldemar Wilczak2, Martina Kluth2, Jakob R Izbicki1, Guido Sauter2, Sarah Minner2, Thorsten Schlomm3,4 and Maria Christina Tsourlakis2 1General, Visceral and Thoracic Surgery Department and Clinic, Hamburg, Germany; 2Institute of Pathology, Hamburg, Germany; 3Martini-Clinic, Prostate Cancer Center, Hamburg, Germany and 4Department of Urology, Section for translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Increased levels of karyopherin a2 (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 (Po0.0001). 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 (Po0.0001 each). Multivariate analysis including all established prognostic criteria available after surgery revealed that the prognostic role of KPNA2 (P ¼ 0.001) was independent of high Gleason grade, advanced pathological tumor stage, high preoperative prostate- specific antigen level and positive surgical margin status (Po0.0001 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 (Po0.0001). 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. Modern Pathology (2014) 27, 96–106; doi:10.1038/modpathol.2013.127; published online 26 July 2013 Keywords: KPNA2; 3p13; prostate cancer; PTEN; 6q15; 5q21; tissue microarray Prostate cancer is the most common malignancy in cause of cancer-related death in men.1 Despite recent men in western societies.1 Even though a conside- advantages in research, the only established pretrea- rable proportion of prostate cancers has a rather tment prognostic parameters currently include indolent course, prostate cancer represents a major Gleason grade, tumor extent on biopsies, preo- perative prostate-specific antigen (PSA) and clinical parameters. These data are statistically powerful but Correspondence: Dr MC Tsourlakis, MD, Institute of Pathology, not sufficient for optimal individual treatment University Medical Center Hamburg-Eppendorf, Martinistrasse decisions. It can be hoped that the analysis of 52, 20246 Hamburg, Germany. molecular features may enable a better individual E-mail: [email protected] 5These authors contributed equally to this work. prediction of tumor aggressiveness in the future. Received 5 December 2012; revised 19 May 2013; accepted 30 Karyopherins are soluble nuclear transport May 2013; published online 26 July 2013 receptors utilizing the nuclear pore complex for www.modernpathology.org Karyopherin a 2 in prostate cancer K Grupp et al 97 transporting cargo proteins and certain RNAs in and Table 1 Pathological and clinical data of the arrayed prostate out of the cell nucleus.2 Karyopherin a 2 (KPNA2) cancers belongs to the karyopherin family and has been described to have an oncogenic role through the No. of patients modulation of the subcellular localization of cargo Study cohort on Biochemical relapse 3 proteins relevant for cancer. KPNA2 is also TMA (n ¼ 11 152) among categories suspected to be involved in cellular proliferation, (n ¼ 1824) differentiation, cell–matrix adhesion, colony forma- tion and migration.4–7 Increased KPNA2 expression Follow-up (months) Mean 53.4 — levels, as compared with normal tissue, have been Median 36.8 — described in various malignancies including breast cancer,8 melanoma,9 ovarian cancer10 and Age (years) astrocytoma.11 o50 318 49 50–60 2.768 460 Upregulation of nuclear KPNA2 protein expres- 60–70 6.548 1.081 sion was described in prostate cancer tissue and 470 1.439 232 KPNA2 expression levels were found to be asso- Pretreatment PSA (ng/ml) ciated with PSA recurrence after radical prostatect- o4 1.407 142 omy in a cohort of 707 primary prostate cancer 4–10 6735 827 patients.4 In vitro experiments demonstrated that 10–20 2159 521 inhibition of KPNA2 reduced proliferation and 420 720 309 4 viability of PC3 cells. In consequence of the detec- pT category (AJCC 2002) tion of the TMPRSS2:ERG fusion prostate cancer is pT2 7.370 570 divided into subsets of fusion-positive and -negative pT3a 2.409 587 pT3b 1.262 618 tumors, which are linked to other genomic altera- pT4 63 49 tions, including deletions of PTEN and 3p13 in fusion-positive as well as deletions of 5q21 and 6q15 Gleason grade 12–19 r3 þ 3 2.859 193 in fusion-negative cancers. As these deletions 3 þ 4 1.565 573 12–19 have all been linked to poor patient prognosis, 4 þ 3 6.183 849 we hypothesize that the prognostic value of KPNA2 Z4 þ 4 482 208 might be modified by the presence or absence of pN category these alterations. To learn more about the potential pN0 6.117 1.126 clinical utility of KPNA2 protein analysis and its pN þ 561 291 association with known key molecular alterations in Surgical margin prostate cancer, a tissue microarray (TMA) contain- Negative 8.984 1.146 ing 11 152 prostate cancer specimens with clinical Positive 1.970 642 follow-up and an attached molecular database was utilized. Our data demonstrate that high KPNA2 Abbreviation: AJCC, American Joint Committee on Cancer. staining is a strong and independent prognostic Note: Numbers do not always add up to 11 152 in the different categories because of cases with missing data. marker in prostate cancer. specimens were reviewed for the purpose of this Materials and methods study and the tumors were marked on the slides. Patients One 0.6-mm tissue core was punched from a preselected area of each tumor and transferred into Radical prostatectomy specimens were evaluable a TMA. The punch site was selected to contain the from 11 152 patients undergoing surgery between highest possible fraction of tumor cells. The tissues 1992 and 2011 at the Department of Urology, and the were distributed among 24 TMA blocks, each Martini Clinics at the University Medical Center containing 144–522 tumor samples. The presence Hamburg-Eppendorf. Follow-up data were available or absence of cancer tissue was validated by for a total of 9628 patients with a median follow-up immunohistochemical AMACR and 34BE12 analy- of 36.8 months (range: 1–228 months; Table 1). PSA sis on adjacent TMA sections. For internal controls, values were measured following surgery and recur- each TMA block also contained various control rence was defined as a postoperative PSA of 0.2 ng/ tissues, including normal prostate tissue. The ml and increasing at first appearance. All prostate molecular database attached to this TMA contained specimens were analyzed according to a standard results on ERG expression in 9628 ERG break-apart procedure, including a complete embedding of fluorescence in situ hybridization (FISH) analysis in the entire prostate for histological analysis.20 6106 (expanded from Minner et al22), and deletion The TMA manufacturing process was described status of 5q21 in 3037,16 6q15 in 3528 (expanded earlier in detail.21 All hematoxylin- and eosin- from Kluth et al15), PTEN in 613017 and 3p13 in stained histological sections from all prostatectomy 1290 (unpublished data) tumors. Modern Pathology (2014) 27, 96–106 Karyopherin a 2 in prostate cancer 98 K Grupp et al Immunohistochemistry Contingency tables and the w2 test were performed to search for associations between molecular Freshly cut TMA sections were immunostained on parameters and tumor phenotype. Survival one day and in one experiment. The primary anti- curves were calculated according to Kaplan–Meier. body specific for KPNA2 (polyclonal; rabbit, Abcam; The log-rank test was applied to detect significant cat. no. ab84440; at 1/150 dilution) was applied, survival differences between groups. Cox propor- slides were deparaffinized and exposed to heat- tional hazards regression analysis was performed induced antigen retrieval for 5 min in an autoclave to test the statistical independence and significance 1 at 121 C in Tris-EDTA buffer (pH 9). Bound antibody between pathological, molecular and clinical was then visualized using the EnVision Kit (Dako). variables. One experienced person analyzed all stainings (KG). KPNA2 expression was predominantly localized in the nucleus, with lower expression levels in the cytoplasm of the cells. Nuclear KPNA2 staining was Results evaluated according to the following scoring system: Technical Issues the staining intensity (0, 1 þ ,2þ and 3 þ ) and the fraction of positive tumor cells were recorded for A total of 3188 of 11 152 arrayed tissue samples each tissue spot. A final immunohistochemistry (28.6%) were non-informative for KPNA2 IHC (IHC) score was built from these parameters as because of the complete lack of tissue or absence described previously:23–25 negative scores had of unequivocal cancer cells.
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