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KLK15 Is a Prognostic Marker for Progression?

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KLK15 Is a Prognostic Marker for Progression? IJC International Journal of Cancer KLK15 is a prognostic marker for progression-free survival in patients with radical prostatectomy Anja Rabien1, Florian R. Fritzsche2,3, Monika Jung1, Angelika To¨lle1, Eleftherios P. Diamandis4, Kurt Miller1, Klaus Jung1,5, Glen Kristiansen2,3y and Carsten Stephan1,3y 1 Department of Urology, Charite´ - Universita¨tsmedizin Berlin, Campus Charite´ Mitte, Berlin, Germany 2 Institute of Pathology, Charite´ - Universita¨tsmedizin Berlin, Campus Charite´ Mitte, Berlin, Germany 3 Institute of Pathology, Universita¨tsspital Zu¨rich, Zu¨rich, Switzerland 4 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada 5 Berlin Institute for Urologic Research, Berlin, Germany In search of biomarkers for prostate cancer, we evaluated the expression of the human kallikrein-related peptidase KLK15 in samples of prostatic adenocarcinomas from radical prostatectomies. Twenty-five pairs of cancerous and adjacent normal prostatic tissue were selected by laser capture microdissection. The tissue was used for quantification of KLK15 mRNA by reverse-transcriptase polymerase chain reaction. Immunohistochemical expression of the KLK15 protein in 193 samples of prostatic adenocarcinoma was analysed in relation to clinicopathological parameters of the patients and disease progression. Expression of KLK15 correlated with the pathological tumour stage and Gleason score of the cases, both at mRNA and at protein level. While mRNA expression in the tumour was elevated, the protein level of KLK15 was reduced compared with adjacent normal tissue and to prostatic intraepithelial neoplasia. Univariate Kaplan-Meier analysis showed a significant association of dichotomised KLK15 levels with disease progression defined by prostate-specific antigen relapse (p 5 0.001). Multivariate analysis according to the Cox proportional hazards regression model identified dichotomised KLK15 expression, corrected for the patient parameters age, preoperative prostate-specific antigen level, pathological tumour stage, Gleason score and surgical margin status, as an independent prognostic factor for poor outcome (inclusion model, hazard ratio 1.802, 95% confidence interval 1.037–3.132, p 5 0.037). We suggest KLK15 as a new independent tumour marker for patients at risk for disease progression after radical prostatectomy. With 15 members up to now, the human kallikrein-related cascade pathways to activate each other, process growth fac- peptidases (KLKs, formerly ‘‘kallikreins’’1 are the largest tor binding proteins and cleave components of the extracellu- group of human serin proteases, localised on chromosome lar matrix.2,3 Naturally designed to regulate cell growth, 19q13.4. Kallikreins act as secreted proteins in proteolytic migration and angiogenesis, KLKs contribute to invasive and metastatic processes in carcinogenesis.4 Several kallikreins are Key words: KLK15, prostate cancer, prognostic marker, RT-PCR, found in the prostate and in the prostate fluid, in which they immunohistochemistry regulate semen liquefaction at ejaculation.3 Characteristic pat- Abbreviations: ALAS1: aminolevulinate synthase 1; CI: confidence terns for prostate cancer were already found for some KLKs, interval; EAU: European Association of Urology; HPRT1: e.g., for the commonly used prostate-specific antigen (PSA, hypoxanthine phosphoribosyl transferase 1; K-ALPHA-1: K-alpha-1 KLK3).4–10 Early Detection and Diagnosis tubulin; KLK: kallikrein-related peptidase; PIN: prostatic Although PSA is in use as serum biomarker for detection intraepithelial neoplasia; PSA: prostate-specific antigen; RT-PCR: of prostate adenocarcinoma and as indicator of the biochemi- reverse-transcriptase polymerase chain reaction cal relapse after radical prostatectomy, its limitations still dis- Additional Supporting Information may be found in the online satisfy regarding sensitivity and specificity.10 Although version of this article. improving, the latter is true as well for different forms or Grant sponsor: Deutsche Forschungsgemeinschaft; combinations of PSA with other parameters.10 Tissue-associ- Grant number: JU 365/6-1/2; Grant sponsor: Sonnenfeld-Stiftung ated biomarkers, which could help to specify diagnosis, prog- DOI: 10.1002/ijc.25435 nosis and therapeutic approaches for prostate cancer, did not History: Received 8 Mar 2010; Accepted 19 Apr 2010; Online 5 reach the level of common clinical use up to now, but there May 2010 already is an example of recent advances in diagnostics. Correspondence to: Anja Rabien, Department of Urology, Research Weaknesses of single biomarkers are compensated in com- Division, Charite´ - Universita¨tsmedizin Berlin, Charite´platz 1, 10117 bining immunohistochemical staining of basal cells (p63) and Berlin, Germany, Tel.: þ49 30 450515035, Fax: þ49 30 450515904, of alpha-methylacyl-CoA racemase (AMACR) with a third E-mail: [email protected] and fourth staining of golgi phosphoprotein 2 (GOLPH2) Int. J. Cancer: 127, 2386–2394 (2010) VC 2010 UICC Rabien et al. 2387 and fatty acid synthase (FASN) to correctly diagnose 99% of Table 1. Clinicopathological characteristics of prostate cancer 1 prostate carcinoma at the Institute for Clinical Pathology, patients Universita¨tsspital Zu¨rich.11 The 3 tissue markers PSA, pros- Patient characteristics tate-specific membrane antigen (PSMA) and the androgen Age (years)2 61 (46–73) receptor are used to assess the metastatic state of prostate Preoperative PSA level (ng/ml)2,3 9.4 (0.5–150) 11 carcinoma patients. Nevertheless, new biomarkers are Follow-up time (months)2 60 (10–188) sought, which could considerably improve the informational PSA defined recurrence content of the material from biopsies or prostatectomies, per- haps avoiding annoying checkups. Discriminative tissue Yes – no. (%) 63 (32.6) markers for cases which will undergo recurrence after radical No – no. (%) 130 (67.4) prostatectomy or which will define survival could avoid over- Time (months)2 27 (2–144) treatment. Therefore, in particular, prognosis of prostate ade- Tumour characteristics n (%) nocarcinoma still needs an update. Since our initial investiga- pT status tions on the youngest member of the human kallikrein-related pT2 108 (56.0) peptidases, KLK15, suggested a suitability as biomarker for prostate cancer,12,13 our retrospective study focused on this pT3 80 (41.5) target in a wider approach. pT4 5 (2.6) 13 In time with our first description of the KLK15 gene, Gleason score the human kallikrein-related peptidase was found as ‘‘pros- 3 7 (3.6%) 14 tin’’ supposed to cleave pro-PSA. KLK15 has an assumed 4 13 (6.7%) trypsin-like activity15 and is up-regulated by steroid hor- 5 29 (15.0%) mones.13,16 It is expressed among others in seminal plasma and in the prostate, where abundant amounts of KLK15 6 30 (15.5%) mRNA were opposite to rather low concentrations of the 7 64 (33.2%) 13,17,18 protein, detected by an immunofluorometric assay. 8 33 (17.1%) Real-time reverse transcriptase polymerase chain reaction 9 16 (8.3%) (RT-PCR) experiments proposed KLK15 as an independent 10 1 (0.5%) favourable prognostic marker for progression-free and overall Surgical margin status survival of breast cancer patients16 and, by contrast, to be an independent unfavourable marker for ovarian cancer.19 Ovar- R0 109 (56.5%) ian carcinomas had elevated levels of KLK15 compared with R1 82 (42.5%) 19 benign ovarian tissues. Analyses of KLK15 mRNA in pros- Rx 2 (1.0%) tate cancer described an increase compared to normal pros- 1193 patients evaluated for immunohistochemical expression of KLK15. tatic tissue as well, associating KLK15 with more aggressive 2Data are presented as median and range (in parentheses). 3Interquartile 12,13 tumours. range (6–15) ng/ml; 15 values were missing. In view of these promising results, we chose a comprehen- sive immunohistochemical approach to the KLK15 protein in prostate cancer, which is closer to practice. Expression of Clinicopathological patient parameters are listed in Table 1 KLK15 should be localised and correlated to clinicopathologi- with follow-up time lasting from the date of surgery to the cal parameters including postoperative PSA levels. Additional recent determination of PSA level. A PSA recurrence, which quantification of KLK15 mRNA in laser microdissected mate- was considered to indicate progression of prostate cancer, was rial should more exactly define the transcriptional expression defined as a persistent increase of PSA to 0.2 ng/ml fol- Early Detection and Diagnosis levels in prostatic adenocarcinoma. lowing the recommendations of the Prostate Cancer Guidelines Update Panel.21 For mRNA analysis, 25 patients with radical prostatecto- Material and Methods mies of the years 2003 and 2004 were included in the study Patients under the conditions as mentioned earlier. The median age One hundred ninety-three patients with prostatic adenocarci- was 62 (range: 46–70 years), the median preoperative PSA noma who underwent radical prostatectomy at the Depart- level was 7.1 ng/ml (range: 1.8–35.1 ng/ml) and the median ment of Urology, Charite´ University Hospital between 1989 follow-up time was 51 months (range: 4–81 months) with 5 and 2001 were included in the immunohistochemical study (20%) cases of PSA defined recurrence. Median time to re- with permission of the local ethics committee. Tumour stages currence was 28 months (range: 2–45 months). The prostate were determined according to L’Union Internationale Contre
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