Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer.
The purpose of our study was to demonstrate that distinct cytogenetic alterations in the most common subtype of renal cell cancer, clear cell renal cell carcinoma (ccRCC), are reflected in protein expression profiles. We performed conventional cytogenetics and immunohistochemical analysis for cytokeratins (CKs) on 126 ccRCCs. Protein expression was evaluated in situ using a semiautomated quantitative system. The results were validated using an independent cohort of 209 ccRCCs with long-term follow-up. Cytogenetic alterations were identified in 96 of 126 ccRCCs, most of them involving chromosome 3 through loss, deletion or translocation. Expression of CKs and E-cadherin in ccRCC was associated with lack of cytogenetic alterations and low nuclear grade. In the validation set, CK7 and CK19 protein expression was associated with better clinical outcome. At the multivariate level, the best model included metastatic status and CK19 expression. Expression microarray analysis on 21 primary ccRCCs and 14 ccRCC metastases identified genes significantly associated with CK7 and CK19 expressing ccRCCs. Two novel ccRCC biomarkers associated with the CK7 positive ccRCC phenotype, PMS2 and MT1-MMP (MMP14), were further validated. We conclude that the variability observed for CK expression in ccRCC can be explained by genetic heterogeneity. Distinct molecular subtypes of ccRCC with prognostic relevance were identified, and the CK7/CK19 expressing subtype is associated with better outcome.
Mertz
Kirsten D
KD
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Demichelis
Francesca
F
Sboner
Andrea
A
Hirsch
Michelle S
MS
Dal Cin
Paola
P
Struckmann
Kirsten
K
Storz
Martina
M
Scherrer
Simone
S
Schmid
Daniel M
DM
Strebel
Räto T
RT
Probst-Hensch
Nicole M
NM
Gerstein
Mark
M
Moch
Holger
H
Rubin
Mark A
MA
D000251:Adenosine Triphosphatases / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D002292:Carcinoma, Renal Cell / Q000737:chemistry* / Q000235:genetics / Q000473:pathology*; D002893:Chromosomes, Human, Pair 3; D020732:Cytogenetic Analysis; D045643:DNA Repair Enzymes / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D053539:Keratin-19 / Q000032:analysis*; D053552:Keratin-7 / Q000032:analysis*; D007680:Kidney Neoplasms / Q000737:chemistry* / Q000473:pathology*; D053511:Matrix Metalloproteinase 14 / Q000032:analysis; D046228:Microarray Analysis; D000070976:Mismatch Repair Endonuclease PMS2; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D013997:Time Factors; D014178:Translocation, Genetic
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D053539:Keratin-19; D053552:Keratin-7; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes