MicroRNA Expression Profiling Distinguishes Conventional and Chromophobe Renal Cell Carcinomas from Normal Renal Parenchyma
DL Zynger, WA LaFramboise, JM Krill-Burger, CM Sciulli, AM Hensler, AM Perepletchikov, LP Kiss, R Dhir, G Cai, AV Parwani, SI Bastacky. University of Pittsburgh Medical Center, Pittsburgh, PA
Background: MicroRNAs (miRNA) are small non-coding RNAs that modulate expression of protein-encoding genes by binding and inactivating messenger RNA. Renal cell carcinoma (RCC) subtypes are traditionally distinguished by morphologic, immunophenotypic, and cytogenetic characteristics. miRNA expression patterns have not been previously reported for RCC subtypes. The aims of this study are to 1) determine if unique miRNA expression profiles are present among 2 RCC subtypes (conventional (CON) and chromophobe (CHR)) and normal renal parenchyma (NRP) and 2) identify specific miRNAs that may contribute to underlying mechanisms of renal tumorigenesis.
Design: Sixteen specimens of frozen, banked human renal tissue with 4 in each group (CON, CHR, NPR) yielded high integrity RNA that was labeled without amplification and hybridized on microarrays (Exiqon, Denmark) covering all annotated miRNAs in the miRBase (1168 probes with 4 replicates/array). Statistically significant differential expression was determined by the Significance Analysis of Microarray (SAM) multiclass test (Q=0.03) and post-hoc t-test of individual transcripts.
Results: Differential expression was observed in 32 miRNAs among the 3 specimen classes. CON specimens exhibited 14 miRNAs increased from 1.6 to 8.4 fold compared to NRP. These miRNAs were not differentially expressed between CHR and NPR. However, CHR samples revealed an additional 14 distinct miRNAs elevated (2.3 to 9.4 fold) versus NPR specimens that were not differentially expressed between CON and NPR specimens. These miRNAs were all expressed at significantly different levels between CON and CHR samples. miR-21 was among the identified miRNAs increased in CON, consistent with upregulation in other malignancies, including breast, colorectal and cervical carcinoma.
Conclusions: The expression pattern obtained from the RCC tumor samples provided an exclusionary signature for each CON and CHR tumor class when compared to NRP, and from each other. Our data suggest that post-translational regulation may contribute to RCC tumorigenesis as well as to the molecular differentiation pathways resulting in histologic subtypes of RCC. We are currently assessing miRNA profiles in papillary RCC and oncocytoma and evaluating messenger RNA profiles in tumors from the corresponding cases to extend the molecular characterization of miRNA expression in renal neoplasia.
Category: Genitourinary (including renal tumors)
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 139, Monday Morning