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Proteomic Distinction of Renal Oncocytomas and Chromophobe Renal Cell Carcinomas Vanessa Drendel1†, Bianca Heckelmann1†, Christoph Schell1, Lucas Kook2, Martin L

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Proteomic Distinction of Renal Oncocytomas and Chromophobe Renal Cell Carcinomas Vanessa Drendel1†, Bianca Heckelmann1†, Christoph Schell1, Lucas Kook2, Martin L Drendel et al. Clin Proteom (2018) 15:25 https://doi.org/10.1186/s12014-018-9200-6 Clinical Proteomics RESEARCH Open Access Proteomic distinction of renal oncocytomas and chromophobe renal cell carcinomas Vanessa Drendel1†, Bianca Heckelmann1†, Christoph Schell1, Lucas Kook2, Martin L. Biniossek2, Martin Werner1,3,5, Cordula A. Jilg3,4* and Oliver Schilling2,3,6* Abstract Background: Renal oncocytomas (ROs) are benign epithelial tumors of the kidney whereas chromophobe renal cell carcinoma (chRCCs) are malignant renal tumors. The latter constitute 5–7% of renal neoplasias. ROs and chRCCs show pronounced molecular and histological similarities, which renders their diferentiation demanding. We aimed for the diferential proteome profling of ROs and early-stage chRCCs in order to better understand distinguishing protein patterns. Methods: We employed formalin-fxed, parafn-embedded samples (six RO cases, six chRCC cases) together with isotopic triplex dimethylation and a pooled reference standard to enable cohort-wide quantitative comparison. For lysosomal-associated membrane protein 1 (LAMP1) and integrin alpha-V (ITGAV) we performed corroborative immu- nohistochemistry (IHC) in an extended cohort of 42 RO cases and 31 chRCC cases. Results: At 1% false discovery rate, we identifed > 3900 proteins, of which > 2400 proteins were consistently quanti- fed in at least four RO and four chRCC cases. The proteomic expression profling discriminated ROs and chRCCs and highlighted established features such as accumulation of mitochondrial proteins in ROs together with emphasizing the accumulation of endo-lysosomal proteins in chRCCs. In line with the proteomic data, IHC showed enrichment of LAMP1 in chRCC and of ITGAV in RO. Conclusion: We present one of the frst diferential proteome profling studies on ROs and chRCCs and highlight dif- ferential abundance of LAMP1 and ITGAV in these renal tumors. Keywords: Renal cell tumors, Formalin-fxation, Parafn embedment, Proteomics, Immunohistochemistry Background overall prognosis is more favourable than for renal Chromophobe renal cell carcinoma (chRCC) consti- clear cell carcinomas with a 5-year survival rate tute 5–7% of renal neoplasias [1]. ChRCC are thought of > 75% [1, 3]. However, this is still a malignant tumor to originate from cell of the distal nephron [2]. Their entity with the potential for recurrence or metastatic spread. Renal oncocytomas (ROs) are benign epithelial tumors of the kidney. They constitute up to 7% of all adult renal tumors [4]. ROs have been first described *Correspondence: Cordula.Jilg@uniklinik‑freiburg.de; oliver. schilling@mol‑med.uni‑freiburg.de as late as 1942 [5] and clinical reports have remained †Vanessa Drendel and Bianca Heckelmann contributed equally to this scarce until the 1970s [6]. Differentiation between RO work and chRCC in pathological routine practice is often 2 Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Stefan Meier Strasse 17, 79104 Freiburg, Germany4 considered challenging [4, 7]. This is because of strong Department of Urology, Medical Center – University of Freiburg, Faculty similarities in morphology, growth pattern and locali- of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, zation of benign ROs and malignant chRCCs. For this Germany Full list of author information is available at the end of the article reason, distinguishing biomarkers are actively being © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Drendel et al. Clin Proteom (2018) 15:25 Page 2 of 15 researched. In this context, system-wide, omics-type Histopathological diagnosis for renal oncocytoma expression profiling studies are emerging as a strong or chromophobe renal cell carcinoma and unbiased approach. Several of such expression Te diagnosis for all RO or chRCC cases used in this studies aimed at a comprehensive differential profiling study was based on histopathologic parameters (cyto- of various renal cell tumors, also including clear cell plasm, cell membrane, perinuclear halo, tumor border renal cell carcinoma (ccRCCs) or papillary renal cell and septae) and corroborated by immunohistochemis- carcinoma. Often, such studies involved only low num- try (IHC) for CD117, cytokeratin-7, and vimentin. Tese bers of RO and chRCC cases and aimed at their col- IHC stainings were part of the routine immunohisto- lective distinction from other renal cell tumors rather pathological diagnosis with the corresponding antibod- than molecularly distinguishing ROs and chRCCs. ies being supplied by Dako (Hamburg, Germany). We Yusenko et al. probed genome alterations and DNA focused on chRCC cases that displayed difuse-membra- copy number variants to specifically differentiate ROs nous expression of cytokeratin-7 whereas its expression and chRCCs. They identified several genomic altera- was largely absent in the RO cases [1, 7]. Moreover, the tions that differ between chRCCs and ROs [8]. A sec- RO and chRCC cases displayed membranous expres- ond genomic study identified differing chromosomal sion of CD117 [7]. Finally, the RO and chRCC cases were abnormalities with regard to chromosome 19 in ROs vimentin-negative [1]. or chRCCs [9]. The resulting gene expression effects affected oxygen sensing. This is an intriguing parallel Tissue collection, sample preparation, liquid to ccRCCs which frequently carry somatic, inactivat- chromatography‑tandem mass spectrometry (LC–MS/MS), ing mutations of the Von Hippel-Lindau gene, ulti- and data analysis mately leading to the expression of hypoxia-related FFPE tissue specimens of six ROs and six chRCCs were genes and promotion of tumorigenesis [10]. On the used as described previously [15, 19], including micro- genomic level, Joshi et al. [11] distinguish two types scopically controlled macrodissection to remove areas of ROs and link chromosomal abnormalities involv- of necrosis, fbrosis, hemorrhage, and infammation. For ing chromosome 1, X or Y, and/or 14 and 21 with the quantitative comparison, triplex isotopic dimethylation potential for progression from RO to chRCC. Rohan of primary amines was employed [20], distinguishing et al. [12] performed a global transcriptomic profil- RO, chRCC, and a pooled mix that serves as a standard ing of ROs and chRCCs. Major expression differences similar to the Super-SILAC approach [21]. Samples were were found with regard to transcript encoding pro- further fractionated by strong cation exchange chroma- teins involved in vesicular transport and cell junction. tography as described [22]. LC–MS/MS was performed On the protein level, multiple protein biomarkers have using a Q-Exactive plus (Termo Scientifc) mass spec- been suggested (reviewed in [4]) but to date there has trometer coupled to an Easy nanoLC 1000 (Termo not been an unbiased, differential proteomic profiling Scientifc) as described previously [18]. MS data were of ROs and chRCCs. However, proteomic profiling is analyzed by MaxQuant version 1.5.28 [23] as described gaining interest for the investigation of malignancies previously [19]. Proteins were only further considered due to the limited correlation between mRNA and pro- if they were identifed and quantifed in at least four tein levels [13, 14]. Formalin-fixed, paraffin-embedded RO samples and four chRCC samples. Due to this strict (FFPE) samples are a valuable resource for proteomic requirement, we also included proteins that were identi- profiling [15–17], enabling retrospective profiling of fed and quantifed by single peptides in individual sam- clinic-pathologically annotated specimens [18, 19]. In ples. Files obtained by MaxQuant were further processed the present study, we employed “FFPE proteomics” for using RStudio v.0.99.446 (R Foundation for Statistical the differential proteomic profiling of RO and chRCC Computing, Vienna, Austria) as previously described cases for which we find noticeable differences. In a [24]. Reverse and potential contaminants entries were larger cohort comprising > 70 RO and chRCC cases, we removed. Ratios were log2 transformed, normalized by corroborate elevated presence of lysosomal-associated centering, and a linear model was ftted using the limma membrane protein 1 in chRCCs and elevated presence package [25]. of integrin alpha-V in ROs. Immunohistochemical analysis Methods IHC analysis was performed with an extended patient Ethics statement cohort, comprising 42 RO cases and 31 chRCC cases. Te study was approved by the Ethics Committee of the IHC was performed for lysosomal-associated membrane University Medical Center Freiburg (311/12). Before protein 1 (LAMP1) and integrin alpha-V (ITGAV). Slices study inclusion, all patient data were anonymized. Drendel et al. Clin Proteom (2018) 15:25 Page 3 of 15 of 2 µm thickness from FFPE tissue samples were pre- to the kidney (T1 or T2). An overview of the patient pared using a Leica RM2255 microtome. Heat induced characteristics is provided in Table 1. antigen retrieval was performed at pH 9.0.
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