title: High cytoplasmic expression of p27(Kip1)  is associated with a worse cancer-specific survival in clear cell renal cell carcinoma.
abstract: What's known on the subject? and What does the study add? The loss of p27(Kip1) correlates with poor prognosis in various human cancers, and was postulated as a biomarker in RCC. Up to now p27(Kip1) analysis in RCC was focused on its nuclear localization. We confirmed higher p27(Kip1) expression in the nucleus and cytoplasm of RCC and correlated high cytoplasmic p27(Kip1) with an unfavourable clinic and a reduced survival.
  
  
  OBJECTIVE
  To analyse the cytoplasmic and nuclear differences of p27(Kip1) expression and localization in benign and clear cell renal cell carcinoma (ccRCC) with regard to overall survival (OS) and cancer-specific survival (CSS). p27(Kip1) is considered to contribute to the progression of ccRCC and is targeted by next generation dual-therapies.
  
  
  METHODS
  In 140 patients, ccRCC and corresponding benign kidney tissue were analyzed for nuclear and cytoplasmic staining of p27(Kip1) by immunohistochemistry using a tissue microarray technique. Staining intensity and percentage of positive stained cells are given as expression scores. p27(Kip1) expression was categorized as high if ccRCC tissue stained stronger than the respective level of the corresponding benign tissue and categorized as low if ccRCC tissue stained less than or equal to the corresponding benign tissue. Differences in OS and CSS were analyzed by log-rank analysis and expression levels were correlated with tumour and patient characteristics using Fisher's exact test.
  
  
  RESULTS
  Cytoplasmatic (mean [sd]: 13.8% [1.2%] vs 10.7% [1.7%]; P= 0.04) and nuclear (mean [sd]: 75.6% [2.7%] vs 13.6% [2.1%]; P < 0.001) staining of p27(Kip1) were significantly stronger in ccRCC tissues compared to benign tissue. High cytoplasmic p27(Kip1) expression was significantly associated with a higher T and N stage, Fuhrman grade and the presence of metastatic disease (P < 0.001). The median follow-up time was 38.2 months. There was no difference in OS between the low and high expression groups, although CSS was significantly lower in patients with high cytoplasmic p27(Kip1) (P < 0.001) and CSS heavily tended to be lower in the nuclear low expression group (P= 0.069).
  
  
  CONCLUSIONS
  High cytoplasmic p27(Kip1) levels in renal cancer tissues are associated with advanced disease and reduced cancer specific survival, whereas low nuclear expression levels appear to be beneficial. The present study corroborates the consideration of cytoplasmic p27(Kip1) for future diagnostic and targeted therapeutic approaches in RCC establishing a potential protective shift of p27(Kip1) from the cytoplasm to the nucleus.
authors: Department of Urology Pathology, Eberhard-Karls-University Tuebingen, Tuebingen, Germany.
authors: Stephan
authors: S
authors: Kruck
authors: Axel S
authors: AS
authors: Merseburger
authors: Joerg
authors: J
authors: Hennenlotter
authors: Marcus
authors: M
authors: Scharpf
authors: Christian
authors: C
authors: Eyrich
authors: Bastian
authors: B
authors: Amend
authors: Karl-Dietrich
authors: KD
authors: Sievert
authors: Arnulf
authors: A
authors: Stenzl
authors: Jens
authors: J
authors: Bedke
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends
chemical_list: D014408:Biomarkers, Tumor; C436291:CDKN1B protein, human; D004273:DNA, Neoplasm; D050760:Cyclin-Dependent Kinase Inhibitor p27