Mining Tissue Microarray Data to Uncover Combinations of Biomarker Expression Patterns that Improve Intermediate Staging and Grading of Clear Cell Renal Cell Cancer

被引:80
作者
Dahinden, Corinne [2 ,3 ]
Ingold, Barbara [1 ]
Wild, Peter [1 ]
Boysen, Gunther [1 ]
Luu, Van-Duc [1 ]
Montani, Matteo [1 ]
Kristiansen, Glen [1 ]
Sulser, Tullio [4 ]
Buehlmann, Peter [2 ,3 ]
Moch, Holger [1 ,3 ]
Schraml, Peter [1 ]
机构
[1] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland
[2] Swiss Fed Inst Technol, Seminar Stat, Zurich, Switzerland
[3] Swiss Fed Inst Technol, Competence Ctr Syst Physiol & Metab Dis, Zurich, Switzerland
[4] Univ Zurich Hosp, Dept Urol, CH-8091 Zurich, Switzerland
基金
瑞士国家科学基金会;
关键词
CARBONIC-ANHYDRASE-IX; TUMOR-SUPPRESSOR GENE; PROGNOSTIC-SIGNIFICANCE; INDEPENDENT PREDICTOR; UP-REGULATION; CARCINOMA; GROWTH; PTEN; P27(KIP1); MUTATION;
D O I
10.1158/1078-0432.CCR-09-0260
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Purpose: Tumor stage and nuclear grade are the most important prognostic parameters of clear cell renal cell carcinoma (ccRCC). The progression risk of ccRCC remains difficult to predict particularly for tumors with organ-confined stage and intermediate differentiation grade. Elucidating molecular pathways deregulated in ccRCC may point to novel prognostic parameters that facilitate planning of therapeutic approaches. Experimental Design: Using tissue microarrays, expression patterns of 15 different proteins were evaluated in over 800 ccRCC patients to analyze pathways reported to be physiologically controlled by the tumor suppressors von Hippel-Lindau protein and phosphatase and tensin homologue (PTEN). Tumor staging and grading were improved by performing variable selection using Cox regression and a recursive bootstrap elimination scheme. Results: Patients with pT2 and pT3 tumors that were p27 and CAIX positive had a better outcome than those with all remaining marker combinations. A prolonged survival among patients with intermediate grade (grade 2) correlated with both nuclear p27 and cytoplasmic PTEN expression, as well as with inactive, nonphosphorylated ribosomal protein S6. By applying graphical log-linear modeling for over 700 ccRCC for which the molecular parameters were available, only a weak conditional dependence existed between the expression of p27, PTEN, CAIX, and p-S6, suggesting that the dysregulation of several independent pathways are crucial for tumor progression. Conclusions: The use of recursive bootstrap elimination, as well as graphical log-linear modeling for comprehensive tissue microarray (TMA) data analysis allows the unraveling of complex molecular contexts and may improve predictive evaluations for patients with advanced renal cancer. Clin Cancer Res; 16(1); 88-98. (C)2010 AACR.
引用
收藏
页码:88 / 98
页数:11
相关论文
共 51 条
[1]
[Anonymous], 1993, An introduction to the bootstrap
[2]
Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer [J].
Atkins, M ;
Regan, M ;
McDermott, D ;
Mier, J ;
Stanbridge, E ;
Youmans, A ;
Febbo, P ;
Upton, M ;
Lechpammer, M ;
Signoretti, S .
CLINICAL CANCER RESEARCH, 2005, 11 (10) :3714-3721
[3]
Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization [J].
Bissig, H ;
Richter, J ;
Desper, R ;
Meier, V ;
Schraml, P ;
Schäffer, AA ;
Sauter, G ;
Mihatsch, MJ ;
Moch, H .
AMERICAN JOURNAL OF PATHOLOGY, 1999, 155 (01) :267-274
[4]
Bui MHT, 2003, CLIN CANCER RES, V9, P802
[5]
Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers [J].
Cairns, P ;
Evron, E ;
Okami, K ;
Halachmi, N ;
Esteller, M ;
Herman, JG ;
Bose, S ;
Wang, SI ;
Parsons, R ;
Sidransky, D .
ONCOGENE, 1998, 16 (24) :3215-3218
[6]
Cairns P, 1997, CANCER RES, V57, P4997
[7]
Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma [J].
Campbell, L. ;
Jasani, B. ;
Edwards, K. ;
Gumbleton, M. ;
Griffiths, D. F. R. .
BRITISH JOURNAL OF CANCER, 2008, 98 (05) :931-940
[8]
SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27 [J].
Carrano, AC ;
Eytan, E ;
Hershko, A ;
Pagano, M .
NATURE CELL BIOLOGY, 1999, 1 (04) :193-199
[9]
Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms - Frequent expression in renal cell carcinoma and endometrial stromal sarcoma [J].
Chu, PG ;
Arber, DA .
AMERICAN JOURNAL OF CLINICAL PATHOLOGY, 2000, 113 (03) :374-382
[10]
The prognostic significance of epidermal growth factor receptor expression in clear-cell renal cell carcinoma: A call for standardized methods for immunohistochemical evaluation [J].
Cohen, David ;
Lane, Brian ;
Jin, Tao ;
Magi-Galluzzi, Cristina ;
Finke, James ;
Rini, Brian I. ;
Bukowski, Ronald M. ;
Zhou, Ming .
CLINICAL GENITOURINARY CANCER, 2007, 5 (04) :264-270