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Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy.

ABSTRACT: Background: While subtyping of the majority of malignant chromophobe renal cell carcinoma (cRCC) and benign renal oncocytoma (rO) is possible on morphology alone, additional histochemical, immunohistochemical or molecular investigations are required in a subset of cases. As currently used histochemical and immunohistological stains as well as genetic aberrations show considerable overlap in both tumors, additional techniques are required for differential diagnostics. Mass spectrometry imaging (MSI) combining the detection of multiple peptides with information about their localization in tissue may be a suitable technology to overcome this diagnostic challenge. Patients and Methods: Formalin-fixed paraffin embedded (FFPE) tissue specimens from cRCC (n=71) and rO (n=64) were analyzed by MSI. Data were classified by linear discriminant analysis (LDA), classification and regression trees (CART), k-nearest neighbors (KNN), support vector machine (SVM), and random forest (RF) algorithm with internal cross validation and visualized by t-distributed stochastic neighbor embedding (t-SNE). Most important variables for classification were identified and the classification algorithm was optimized. Results: Applying different machine learning algorithms on all m/z peaks, classification accuracy between cRCC and rO was 85%, 82%, 84%, 77% and 64% for RF, SVM, KNN, CART and LDA. Under the assumption that a reduction of m/z peaks would lead to improved classification accuracy, m/z peaks were ranked based on their variable importance. Reduction to six most important m/z peaks resulted in improved accuracy of 89%, 85%, 85% and 85% for RF, SVM, KNN, and LDA and remained at the level of 77% for CART. t-SNE showed clear separation of cRCC and rO after algorithm improvement. Conclusion: In summary, we acquired MSI data on FFPE tissue specimens of cRCC and rO, performed classification and detected most relevant biomarkers for the differential diagnosis of both diseases. MSI data might be a useful adjunct method in the differential diagnosis of cRCC and rO.

SUBMITTER: Kriegsmann M

PROVIDER: S-EPMC7477404 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy.

Kriegsmann Mark M Casadonte Rita R Maurer Nadine N Stoehr Christine C Erlmeier Franziska F Moch Holger H Junker Klaus K Zgorzelski Christiane C Weichert Wilko W Schwamborn Kristina K Deininger Sören-Oliver SO Gaida Matthias M Mechtersheimer Gunhild G Stenzinger Albrecht A Schirmacher Peter P Hartmann Arndt A Kriegsmann Joerg J Kriegsmann Katharina K

Journal of Cancer 20200821 20

<b>Background:</b> While subtyping of the majority of malignant chromophobe renal cell carcinoma (cRCC) and benign renal oncocytoma (rO) is possible on morphology alone, additional histochemical, immunohistochemical or molecular investigations are required in a subset of cases. As currently used histochemical and immunohistological stains as well as genetic aberrations show considerable overlap in both tumors, additional techniques are required for differential diagnostics. Mass spectrometry ima ...[more]

PMID: 32922548

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Project description:BACKGROUND: Chromophobe 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. METHODS: Gene 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. RESULTS: A 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. CONCLUSIONS: Gene 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.

Project description:The present techniques of clinical and histopathological diagnosis hardly distinguish chromophobe renal cell carcinoma (ChRCC) from renal oncocytoma (RO). To identify differentially expressed genes (DEGs) as effective biomarkers for diagnosis and prognosis of ChRCC and RO, three mRNA microarray datasets (GSE12090, GSE19982, and GSE8271) were downloaded from the GEO database. Functional enrichment analysis of DEGs was performed by DAVID. STRING and Cytoscape were applied to construct the protein-protein interaction (PPI) network and key modules of DEGs. Visualized plots were conducted by the R language. We downloaded clinical data from the TCGA database and the influence of key genes on the overall survival of ChRCC was performed by Kaplan-Meier and Cox analyses. Gene set enrichment analysis (GSEA) was utilized in exploring the function of key genes. A total of 79 DEGs were identified. Enrichment analyses revealed that the DEGs are closely related to tissue invasion and metastasis of cancer. Subsequently, 14 hub genes including ESRP1, AP1M2, CLDN4, and CLDN7 were detected. Kaplan-Meier analysis indicated that the low expression of CLDN7 and GNAS was related to the worse overall survival in patients with ChRCC. Univariate Cox analysis showed that CLDN7 might be a helpful biomarker for ChRCC prognosis. Subgroup analysis revealed that the expression of CLDN7 showed a downtrend with the development of the clinical stage, topography, and distant metastasis of ChRCC. GSEA analysis identified that cell adhesion molecules cams, B cell receptor signaling pathway, T cell receptor signaling pathway, RIG-I like receptor signaling pathway, Toll-like receptor signaling pathway, and apoptosis pathway were associated with the expression of CLDN7. In conclusion, ESRP1, AP1M2, CLDN4, PRSS8, and CLDN7 were found to distinguish ChRCC from RO. Besides, the low expression of CLDN7 was closely related to ChRCC progression and could serve as an independent risk factor for the overall survival in patients with ChRCC.

Dataset Information

Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy.

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Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy.

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