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Gene Expression Profiling Separates Chromophobe Renal Cell Carcinoma from Oncocytoma and Identifies Vesicular Transport and Cell

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Gene Expression Profiling Separates Chromophobe Renal Cell Carcinoma from Oncocytoma and Identifies Vesicular Transport and Cell Human Cancer Biology Gene Expression Profiling Separates Chromophobe Renal Cell Carcinoma from Oncocytoma and Identifies Vesicular Transport andCellJunctionProteinsasDifferentiallyExpressedGenes Stephen Rohan,1Jiangling J. Tu,1Jean Kao,1Piali Mukherjee,2 Fabien Campagne,2 Xi K. Zhou,3 Elizabeth Hyjek,1Miguel A. Alonso,4 and Yao-Tseng Chen1 Abstract Purpose:To compare gene expression profiles of chromophobe renal cell carcinoma (RCC) and benign oncocytoma, aiming at identifying differentially expressed genes. Experimental Design: Nine cases each of chromophobe RCC and oncocytoma were analyzed by oligonucleotide microarray. Candidate genes that showed consistent differential expression were validated by reverse transcription-PCR using 25 fresh-frozen and 15 formalin-fixed, paraffin-embedded tumor samples. Immunohistochemical analysis was also done for two selected gene products, claudin 8 and MAL2. Results: Unsupervised hierarchical clustering separated the chromophobe RCC and oncocy- toma into two distinct groups. By a combination of data analysis approaches, we identified 11 candidate genes showing consistent differential expression between chromophobe RCC and oncocytoma. Five of these genes, AP1M2, MAL2, PROM2, PRSS8,andFLJ20171,wereshown to effectively separate these two tumor groups by quantitative reverse transcription-PCR using fresh tissue samples, with similar trends seen on formalin-fixed tissues. Immunohistochemical analysis revealed selective expression of MAL2 and claudin 8 in distal renal tubules, with MAL2 antibody showing differential expression between chromophobe RCC and oncocytoma. Functional analyses suggest that genes encoding tight junction proteins and vesicular membrane trafficking proteins, normally expressed in distal nephrons, are retained in chromophobe RCC and lost or consistently down-regulated in oncocytoma, indicating that these two tumor types, believed to be both derived from distal tubules, are likely distinctive in their histogenesis. Conclusions: We showed that chromophobe RCC and oncocytoma are distinguishable by mRNA expression profiles and a panel of gene products potentially useful as diagnostic markers were identified. Renal cell carcinoma (RCC) is a heterogeneous group of ered to have better prognosis than conventional clear cell malignancy, and clear cell, papillary, and chromophobe RCC carcinoma (2), is malignant and can potentially be aggressive. are the major subtypes (1). Of these, the chromophobe RCC, The similarity between chromophobe carcinoma and onco- constituting 5% to 10%, is the least common and has cytoma likely reflects their shared histogenesis from the inter- morphologic features that often overlap with oncocytoma, a calated cells of the distal tubules, a notion postulated based benign neoplasm. The distinction between these two tumors is on ultrastructural findings (3). This similarity was further clinically important, as chromophobe RCC, although consid- supported by the recent cDNA or oligonucleotide microarrays in which these two tumor types could not be reliably separated. In contrast, chromophobe carcinoma and oncocytoma as a Authors’ Affiliations: 1Department of Pathology and Laboratory Medicine, group showed distinctive microarray profiles, easily separated 2Institute for Computational Biomedicine, and 3Department of Public Health, Weill from clear cell and papillary RCC (4–8). 4 Medical College of Cornell University, New York, New York; and Centro de Despite these similarities, biological differences between these BiologI¤a Molecular ‘‘Severo Ochoa,’’ Consejo Superior de Investigaciones two entities are unequivocal. Cytogenetic evidence was most CientI¤ficas and Universidad Auto¤ noma de Madrid, Madrid, Spain Received 5/24/06; revised 8/8/06; accepted 8/31/06. compelling, with chromophobe RCC showing hypodiploidy, Grant support: Ministerio de Educacio¤ n y Ciencia grants BMC2003-03297, often with monosomy of chromosomes 1, 2, 6, 10, 13, 17, and BFU2006-01925, and GEN2003-20662-C07-02 (M.A. Alonso) and an 21 (9–11). In comparison, oncocytomas often display mixed institutional grant from the Fundacio¤ nRamo¤ n Areces to Centro de BiologI¤a karyotypes, with loss of chromosomes Y and 1 often observed (12). Molecular ‘‘Severo Ochoa.’’ The costs of publication of this article were defrayed in part by the payment of page Additional differences between chromophobe RCC and charges. This article must therefore be hereby marked advertisement in accordance oncytoma were observed in immunohistochemical studies. For with 18 U.S.C. Section 1734 solely to indicate this fact. example, kidney-specific cadherin and epithelial cell adhesion Requests for reprints: Yao-Tseng Chen, Department of Pathology, Weill Medical molecule were shown in one study to be expressed in all, or College of Cornell University, Box 69, 1300 York Avenue, New York, NY 10021. Phone: 212-746-6472; Fax: 212-746-8166; E-mail: [email protected]. almost all, chromophobe RCC, but rarely in oncocytoma (13). F 2006 American Association for Cancer Research. Although this finding was challenged by later studies (14), other doi:10.1158/1078-0432.CCR-06-1268 markers such as cytokeratin 7, parvalbumin, and claudin 7 were www.aacrjournals.org 6937 Clin Cancer Res 2006;12(23) December 1, 2006 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2006 American Association for Cancer Research. Human Cancer Biology Table 1. Differentially expressed genes (67 probe sets, corresponding to 57 genes) with P values of <0.05 and fold change >1.5 Common name GenBank ID Fold change P Description Genes overexpressed in chromophobe RCC TMC4 BE645551 5.902 0.000116 transmembrane channel-like 4 AP1M2 NM_005498 5.196 0.0119 adaptor-related protein complex 1, A2 subunit AP1M2 AA910946 3.560 0.0119 adaptor-related protein complex 1, A2 subunit EPB41L4B NM_019114 2.862 0.0119 erythrocyte membrane protein band 4.1 like 4B CENTA1 AW050627 2.428 0.0119 centaurin, alpha 1 (N.A.) AW302207 2.020 0.0119 transcribed sequences SH3MD2 AI686957 1.636 0.0119 SH3 multiple domains 2 FLJ20171 NM_017697 5.786 0.0127 hypothetical protein FLJ20171 CLDN8 AL049977 11.890 0.0129 claudin 8 SPINT1 NM_003710 5.799 0.0229 serine protease inhibitor, Kunitz type 1 C14orf114 NM_018199 1.581 0.0229 chromosome 14 open reading frame 114 MAL2 AL117612 29.340 0.0238 mal, T-cell differentiation protein 2 MANBA NM_005908 1.929 0.0238 mannosidase, hA, lysosomal SLC27A1 BF056007 1.859 0.0238 solute carrier family 27 (fatty acid transporter), member 1 C14orf87 AA133341 1.501 0.0238 chromosome 14 open reading frame 87 (N.A.) AI191905 4.740 0.024 transcribed sequences LOC196264 AA772172 1.809 0.024 hypothetical protein LOC196264 MGC21874 AI862537 1.754 0.024 transcriptional adaptor 2 (ADA2 homologue, yeast)-h TJP3 NM_014428 1.573 0.024 tight junction protein 3 (zona occludens 3) CLDN7 NM_001307 5.559 0.0298 GABA(A) receptor-associated protein CDS1 NM_001263 4.756 0.0298 CDP-diacylglycerol synthase 1 TJP3 AC0059542.893 0.0298 tight junction protein 3 (zona occludens 3) DKFZP566J2046 AW070436 2.010 0.0298 hypothetical protein DKFZp566J2046 EPS8L1 BC004907 1.650 0.0298 EPS8-like 1 FLJ21918 NM_024939 1.945 0.0333 hypothetical protein FLJ21918 LRRC1 NM_018214 2.236 0.0379 leucine-rich repeat containing 1 STX3A BE966922 2.488 0.0383 NIH_MGC_72 Homo sapiens cDNA clone IMAGE:3915610 FLJ20171 BF001941 19.180 0.0405 hypothetical protein FLJ20171 PVALB NM_002854 4.815 0.0405 parvalbumin (N.A.) AI038402 2.501 0.0438 Transcribed seq. similar to A57377 transcription factor NFATx CAPN1 NM_005186 1.807 0.044 calpain 1, (A/l) large subunit C14orf108 NM_018229 2.445 0.0442 chromosome 14 open reading frame 108 CDS1 AW304313 2.334 0.046 CDP-diacylglycerol synthase 1 TACSTD1 NM_002354 3.307 0.0461 tumor-associated calcium signal transducer 1 CA2 M36532 2.733 0.0461 carbonic anhydrase II FLJ36445 AA827649 2.099 0.0461 hypothetical protein FLJ36445 SLC16A7 AW975728 2.238 0.047 solute carrier family 16, member 7 MDA5 NM_022168 1.671 0.047 melanoma differentiation associated protein-5 C14orf108 AW137526 1.984 0.0483 chromosome 14 open reading frame 108 C14orf125 BF435286 1.682 0.0485 chromosome 14 open reading frame 125 SH3YL1 NM_015677 2.916 0.0493 SH3 domain containing, Ysc84-like 1 HOOK2 NM_013312 2.629 0.0493 hook homologue 2 (Drosophila) FLJ34633 AA573775 2.072 0.0494 hypothetical protein FLJ34633 (Continued on the following page) also described as preferentially expressed in chromophobe RCC following an Institutional Review Board–approved protocol. The H&E over oncocytoma (4, 15–17). In contrast, S100 protein was slides on all cases were reviewed by one of us (J.J.T.), and only found to be preferentially expressed in oncocytoma (18). The histologically unequivocal cases were included. clinical diagnostic usefulness of these markers, however, needs to RNA extraction from fresh-frozen and paraffin-embedded tissues. Total RNA was extracted from fresh tissues using RNeasy mini kit be further confirmed by additional studies. (Qiagen, Valencia, CA). Approximately 30 mg of fresh tissues were Based on these observations, it is believed that these two used for each sample. For extraction of RNA from paraffin- tumors are biologically distinct, but no unequivocal distinguish- embedded tissue, the Optimum FFPE RNA isolation kit (Ambion, ing markers have been defined. In this study, we did oligonucle- Austin, TX) was used with materials derived from four 8-Am otide microarray analysis to search for such biological markers, sections. The nontumor areas on the slides were manually
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