Comprehensive microRNA Profiling in the Spectrum of Kidney Tumors: The Promise of Molecular Signatures for Cancer Subtype Diagnosis, Prognosis and Directed Therapy
BA Walter Rodriguez, VA Valera Romero, L Teller, M Sobel, M Linehan, MJ Merino. National Cancer Institute, National Insitutes of Health, Bethesda
Background: microRNAs are small non-coding RNAs which have been shown to regulate gene expression. Through the modulation of targeted genes, miRNAs may act either as oncogenes or tumor suppressor genes. The expression pattern has also been used to differentiate cancer subtypes. In renal cell carcinoma (RCC), as a highly heterogeneous entity, the miRNA expression pattern can help not only to differentiate different histologic subtypes but also to elucidate the predisposing molecular changes.
Design: Fresh frozen tumor and normal kidney samples from 35 RCC patients were used for analysis. Morphology included clear cell (both sporadic and VHL), Papillary type I, Chromophobe, Oncocytomas, Papillary type II (HLRCC), TSC2 and SDH-C kidney tumors. miRNAs were extracted after needle microdissection and used for both microarray and PCR array profiling. Differentially expressed miRNAs for each of the histologic subtypes as compared to normal kidney were defined as those with a two-fold change and a false discovery rate <1%. Supervised and unsupervised clustering were used to evaluate the role of these histology-specific miRNAs for the diagnosis of RCC.
Results: We identified unique signatures for each histologic subtype of kidney tumor. Expression values for downregulated miRNAs ranged from 0.3-fold (in VHL-clear cell RCC) up to 0.393 fold (in Pap-II HLRCC tumors). Commonly lost miRNAs in clear cell tumors (both sporadic and clear cell) included miR-184 and miR-206, while miR-122 and -143 were the most commonly downregulated in Papillary type I tumors. For the upregulated miRNAs, fold-changes ranged from 2.058 up to 144-fold. Most differentially expressed genes were from HLRCC Pap-II cases. Overexpressed miRNAs included miR-92a in clear cell RCC (2.28-fold, p<0.001), miR-183 in Pap-I (29-fold), miR-10a and -10b in Pap-II tumors (240-fold and 290-fold), miR-203 in chromophobe tumors and miRNas 210/let7i in TSC2 renal tumors.
Conclusions: miRNA profiling in kidney tumors demonstrates unique expression patterns for each histologic subtype. While this microRNA signature can reflect differences in the underlying and unique molecular changes for each subtype, it can also prove useful for supporting the differential diagnosis when definitive classification is doubtful.
Category: Genitourinary (including renal tumors)
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 143, Monday Morning