Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma

Abstract

BackgroundChromophobe renal cell carcinoma (chRCC) and renal oncocytoma are two distinct but closely related entities with strong morphologic and genetic similarities. While chRCC is a malignant tumor, oncocytoma is usually regarded as a benign entity. The overlapping characteristics are best explained by a common cellular origin, and the biologic differences between chRCC and oncocytoma are therefore of considerable interest in terms of carcinogenesis, diagnosis and clinical management. Previous studies have been relatively limited in terms of examining the differences between oncocytoma and chromophobe RCC.MethodsGene expression profiling using the Affymetrix HGU133Plus2 platform was applied on chRCC (n = 15) and oncocytoma specimens (n = 15). Supervised analysis was applied to identify a discriminatory gene signature, as well as differentially expressed genes. High throughput single-nucleotide polymorphism (SNP) genotyping was performed on independent samples (n = 14) using Affymetrix GeneChip Mapping 100 K arrays to assess correlation between expression and gene copy number. Immunohistochemical validation was performed in an independent set of tumors.ResultsA novel 14 probe-set signature was developed to classify the tumors internally with 93% accuracy, and this was successfully validated on an external data-set with 94% accuracy. Pathway analysis highlighted clinically relevant dysregulated pathways of c-erbB2 and mammalian target of rapamycin (mTOR) signaling in chRCC, but no significant differences in p-AKT or extracellular HER2 expression was identified on immunohistochemistry. Loss of chromosome 1p, reflected in both cytogenetic and expression analysis, is common to both entities, implying this may be an early event in histogenesis. Multiple regional areas of cytogenetic alterations and corresponding expression biases differentiating the two entities were identified. Parafibromin, aquaporin 6, and synaptogyrin 3 were novel immunohistochemical markers effectively discriminating the two pathologic entities.ConclusionsGene expression profiles, high-throughput SNP genotyping, and pathway analysis effectively distinguish chRCC from oncocytoma. We have generated a novel transcript predictor that is able to discriminate between the two entities accurately, and which has been validated both in an internal and an independent data-set, implying generalizability. A cytogenetic alteration, loss of chromosome 1p, common to renal oncocytoma and chRCC has been identified, providing the opportunities for identifying novel tumor suppressor genes and we have identified a series of immunohistochemical markers that are clinically useful in discriminating chRCC and oncocytoma.

DNA methylation profiling distinguishes histological subtypes of renal cell carcinoma

“…18 Using a combination of gene expression and high throughput SNP platforms, Tan et al generated a probe signature that could discriminate chromophobe RCC and renal oncocytomas. 19 Petillo et al identified a unique miRNA signature for clear cell, papillary, chromophobe RCC and renal oncocytoma. 20 There is growing evidence that not only genetic but also epigenetic changes play important roles in human malignancy.…”

Copy number profiling in von hippel‐lindau disease renal cell carcinoma

“…Biallelic inactivation of the VHL TSG is a critical and early event in the pathogenesis of cRCC in VHL disease and in many sporadic cRCC; however, additional genetic and epigenetic events are required for the development of cRCC. Recently high resolution genome wide copy number analysis and high throughput sequencing of candidate genes have been employed to delineate the ''post-VHL inactivation events'' that occur in the development of sporadic RCC (Beroukhim et al, 2009;Dalgliesh et al, 2010;Tan et al, 2010). However, RCC is clinically and histopathologically heterogeneous.…”

Effects of Parafibromin Expression on the Phenotypes and Relevant Mechanisms in the DLD-1 Colon Carcinoma Cell Line

“…It was found that parafibromin expression was inversely linked to tumor size, pathologic stage, and lymphovascular invasion of breast carcinomas (Selvarajan et al, 2008). Another study showed that parafibromin was a novel immunohistochemical markers effectively discriminating chromophobe renal cell carcinoma and renal oncocytoma (Tan et al, 2010). In our previous work, it was found that down-regulated parafibromin expression might contribute to the pathogenesis, growth, invasion and metastasis and be regarded as a good marker to indicate the poor prognosis of gastric or colorectal carcinoma patients Zheng et al, 2011).…”