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Klinik-Labor-Besprechung 20.11.2006 Juliane Schmidt & Catharina Rippel & Susanne Füssel

Comparative quantitative evaluation of the XIAP, survivin & Ki67 transcript levels in urine & tissue samples of bladder cancer patients. Klinik-Labor-Besprechung 20.11.2006 Juliane Schmidt & Catharina Rippel & Susanne Füssel Woei-Yun Siow & Axel Meye & Oliver W. Hakenberg. Introduction.

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Klinik-Labor-Besprechung 20.11.2006 Juliane Schmidt & Catharina Rippel & Susanne Füssel

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  1. Comparative quantitative evaluation of the XIAP, survivin & Ki67 transcript levels in urine & tissue samples of bladder cancer patients Klinik-Labor-Besprechung 20.11.2006 Juliane Schmidt & Catharina Rippel & Susanne Füssel Woei-Yun Siow & Axel Meye & Oliver W. Hakenberg

  2. Introduction • Bladder cancer (BCa): 5th most common cancer in european men & 6th leading cause of death • Cystoscopy & urine cytology: current gold standards for diagnosis & surveillance of BCa • no ideal tumor marker for non-invasive diagnostic & surveillance at the moment (e.g. NMP22, BTA)

  3. Objectives • to establish methods for reliable and quantitative transcript measurements in urine and tissue specimens • to determine suitability of transcript levels of different BCa-related genes in urine samples as diagnostic, surveillance and prognostic markers of BCa • to analyze marker expression in corresponding BCatissue specimens in comparison to urine samples • to compare the utility of Survivin to other potential tumor markers e.g. Ki67 and XIAP

  4. BCa-related genes • Survivin & XIAP: inhibitor of apoptosis proteins (IAP) • Ki67:proliferation marker, essential for cell cycle progression • selectively over-expressed in most human malignancies incl. BCa • association between over-expression and higher stage & grade and with poor prognosis in many tumor types incl. BCa • suitable markers and therapeutic targets for BCa (e.g. own studies) • recent studies: transcript levels of Surivin and Ki67 useful for non-invasive BCa detection in urine samples

  5. Materials & Methods 1 • prospective study, January - June 2006 (first study group), continuation • Inclusion criteria: • patients undergoing transurethral resection (TUR) for newly diagnosed BCa, recurrent BCa & cystoscopically suspicious bladder lesions • Exclusion criteria: • patients with PCa • Controls • BPH patients • cystitis patients • healthy volunteers

  6. Materials & Methods 2 • BCa patients • pre-operative urine sample • intra-operative tumor tissue & “normal appearing” bladder mucosa • post-operative urine sample (1 POD)  for each session of TUR • Controls • 1 urine sample

  7. Materials & Methods 3 • preparation of cellular components from urine • isolation of totalRNA and cDNA-synthesis • quantitative PCR of transcript levels of Survivin, XIAP & Ki67 and the reference gene TBP in urine and tissue samples • relative expression levels (internal normalization to TBP) of Survivin, XIAP & Ki67 correlated with clinicopathological data

  8. BCa patients 1 • 65 recruited between Jan. and June 2006 • 6 pts with both BCa & PCa, excluded from analysis  59 pts analyzed • age (median) = 69 yrs (34 – 89) • M:F = 39: 20 (66.1% : 33.9%) • newly dx : BCa recurr. = 54: 5 (91.5% : 8.5%) • PSA (median; 36 pts) = 0.90 (0.16 – 12.54)

  9. BCa patients 2 Stage @ diagnosis (59) • no tumour (11) 18.6% • superficial (38) = Ta+T1 64.5% • invasive (10) = T2 16.9% Grade @ diagnosis (59) • no tumour (11) 18.6% • low (14) = G1 23.8% • high (34) = G2+G3 57.6% Cis • pos. : neg. = 5 : 54 (8.5% : 91.5%) • All pts with cis harbour high grade (G2/ G3) disease as well.

  10. BCa patients 3  59 primary TUR  42 second op (33 sec TUR, 9 cystec) • 8 third op (6 tertiary TUR, 2 cystec) Controls

  11. Results 1 • 2 reference genes tested: TBP better than HPRT • urine specimens: negative correlation between reference gene expression & urinary contamination by RBCs, WBCs & bacteria  many samples with negative reference gene results (e.g. pts with infection or hematuria or post-TUR urines) • tissue specimens: less samples with negative reference gene results • target validation in tissue specimens, comparison Tu  Tf • target evaluation in urine specimens with regard to BCa diagnosis

  12. Tumor markers in unpaired tissue specimens Median values presented.

  13. Ki67 / TBPin unpaired tissue specimens

  14. XIAP / TBP in unpaired tissue specimens

  15. SVV / TBP for unpaired tissue specimens

  16. Tumor markers in paired tissue specimens Median values presented.

  17. Tumor markers in urine specimens of BCa patients & controls For healthy controls the absent values were substituted by zero Median values presented.

  18. Ki67 / TBPin urine of BCa patients & controls

  19. XIAP / TBP in urine of BCa patients & controls

  20. SVV / TBP in urine of BCa patients & controls

  21. Tumor markers in urine vs BCa stage Median values presented.

  22. Tumor markers in urine vs BCa grade Median values presented.

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