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Virtual Karyotyping with SNP Microarrays Reduces Uncertainty In Diagnostic Pathology BioMed Central Research Open Access Virtual karyotyping with SNP microarrays reduces uncertainty in the diagnosis of renal epithelial tumors Jill M Hagenkord1, Anil V Parwani1, Maureen A Lyons-Weiler2, Karla Alvarez3, Robert Amato3, Zoran Gatalica4, Jose M Gonzalez-Berjon5, Leif Peterson3, Rajiv Dhir1 and Federico A Monzon*3,5,6 Address: 1Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA, 2Clinical Genomics Facility, University of Pittsburgh, Pittsburgh, PA, USA, 3Department of Pathology, The Methodist Hospital Research Institute, Houston, TX, USA, 4Department of Pathology, Creighton University Medical Center, Omaha, NE, USA, 5Department of Pathology, The Methodist Hospital, Houston, TX, USA and 6Pathology, Weill Medical College of Cornell University, New York, NY, USA Email: Jill M Hagenkord - [email protected]; Anil V Parwani - [email protected]; Maureen A Lyons- Weiler - [email protected]; Karla Alvarez - [email protected]; Robert Amato - [email protected]; Zoran Gatalica - [email protected]; Jose M Gonzalez-Berjon - [email protected]; Leif Peterson - [email protected]; Rajiv Dhir - [email protected]; Federico A Monzon* - [email protected] * Corresponding author Published: 6 November 2008 Received: 18 September 2008 Accepted: 6 November 2008 Diagnostic Pathology 2008, 3:44 doi:10.1186/1746-1596-3-44 This article is available from: http://www.diagnosticpathology.org/content/3/1/44 © 2008 Hagenkord et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Renal epithelial tumors are morphologically, biologically, and clinically heterogeneous. Different morphologic subtypes require specific management due to markedly different prognosis and response to therapy. Each common subtype has characteristic chromosomal gains and losses, including some with prognostic value. However, copy number information has not been readily accessible for clinical purposes and thus has not been routinely used in the diagnostic evaluation of these tumors. This information can be useful for classification of tumors with complex or challenging morphology. 'Virtual karyotypes' generated using SNP arrays can readily detect characteristic chromosomal lesions in paraffin embedded renal tumors and can be used to correctly categorize the common subtypes with performance characteristics that are amenable for routine clinical use. Methods: To investigate the use of virtual karyotypes for diagnostically challenging renal epithelial tumors, we evaluated 25 archived renal neoplasms where sub-classification could not be definitively rendered based on morphology and other ancillary studies. We generated virtual karyotypes with the Affymetrix 10 K 2.0 mapping array platform and identified the presence of genomic lesions across all 22 autosomes. Results: In 91% of challenging cases the virtual karyotype unambiguously detected the presence or absence of chromosomal aberrations characteristic of one of the common subtypes of renal epithelial tumors, while immunohistochemistry and fluorescent in situ hybridization had no or limited utility in the diagnosis of these tumors. Conclusion: These results show that virtual karyotypes generated by SNP arrays can be used as a practical ancillary study for the classification of renal epithelial tumors with complex or ambiguous morphology. Page 1 of 13 (page number not for citation purposes) Diagnostic Pathology 2008, 3:44 http://www.diagnosticpathology.org/content/3/1/44 Background including comparative genomic hybridization (CGH)[6], Each year in the United States, there are approximately array CGH [7], and SNP arrays [8]. Array CGH has been 31,900 cases of kidney and upper urinary tract cancer that used to accurately classify RCCs by histologic type, based account for approximately 3% of adult malignancies, and on the specific genetic alterations described above [7,9]. result in more than 11,900 deaths [1]. The most common However, most studies have been descriptive and have not types of renal epithelial tumors are clear cell renal cell car- attempted to develop and validate a molecular diagnostic cinoma (RCC) (75%), papillary RCC (10%), chromo- tool for chromosome copy number analysis to classify phobe RCC (5%), and benign oncocytoma (5%)[2]. diagnostically challenging tumors. In addition, a limita- Correct pathological classification is critical for prognosis, tion of array CGH is that it cannot detect regions of 'copy management, therapy, and eligibility for clinical trials. neutral LOH' or acquired uniparental disomy (UPD) Classification of renal epithelial tumors is primarily based which has been reported to constitute 50–80% of the on cytologic appearance, cell type of origin, and growth LOH in human cancers [10-13]. SNP arrays been used suc- pattern. Morphological distinction among the renal cell cessfully to detect structural variations in several types of tumor subtypes is generally straightforward after routine cancer, including RCC [8,11,14-19]. These arrays are sim- pathologic examination of the tissue. However, a subset ilar to array CGH in that fragmented genomic DNA is of cases are ultimately diagnosed as renal cell carcinoma, amplified and applied to an array with the chromosomes unclassified, due to the presence of non-specific features reassembled in silico. However, instead of cDNA or BAC that can be seen in all of the subtypes (such as granular, probes, SNP arrays use synthesized oligonucleotide oncocytic or sarcomatoid morphology) [3] or the pres- probes optimized to identify specific alleles at each SNP ence of more than one subtype in the same tumor [2]. locus. Thus, in addition to copy number information, SNP arrays also provide genotypes which can be used to Specific genetic abnormalities have been found in the dif- determine regions of LOH. Other advantages include the ferent types of renal cell tumors and have been well char- ability to use either fresh or paraffin-embedded tissues acterized in the literature [4]. More than 98% of clear cell [20-22], relatively low cost, good manufacturing practices, RCC show deletions in the p arm of chromosome 3, while and that they are amenable to scalability and automation. papillary RCC usually presents with trisomies of chromo- Combined genome-wide copy number and LOH analysis somes 7 & 17 and/or loss of chromosome Y. Chromo- with SNP arrays has also been referred to as "molecular phobe RCC is characterized by a hypodiploid allelokaryotyping" [23] and SOMA (SNP oligonucleotide chromosomal complement with monosomies of chromo- microarray analysis) [24]. The potential clinical applica- somes 1, 2, 6, 10, 13, 17 and 21. Oncocytoma shows tions for SNP microarrays in molecular oncology assays either normal chromosomes or copy number alterations are evident and we consider that this platform is suitable in chromosome 1. Although the chromosomal alterations for diagnostic/prognostic test development for chromo- that characterize each subtype of renal epithelial neo- some copy number analysis of human tumors. plasms have been known for some time, this knowledge has not been routinely utilized in the diagnostic evalua- The purpose of this study was to assess the utility of SNP tion of these tumors. More than a decade ago, Steiner and array virtual karyotypes in the diagnosis of renal epithelial Sidransky proposed the use of loss of heterozygosity tumors that are not readily classifiable by standard his- (LOH) analysis with microsatellites to detect specific topathologic evaluation. Our previous work has shown chromosomal deletions in renal tumors [5]. However, that characteristic genetic lesions are readily identifiable these assays have not been incorporated into clinical prac- in morphologically classic renal epithelial tumors [8]. tice. Metaphase karyotyping can be used to detect these Here, we extend the classic morphology cohort (n = 50) as characteristic chromosomal lesions but it is not routinely well as assess the performance of the SNP array virtual used for diagnosis of renal tumors because fresh tissue is karyotype on 25 morphologically challenging renal epi- typically not available and solid tumors often grow poorly thelial tumors. Our results indicate that virtual karyotypes in culture. In addition karyotypes from solid tumors are can be used to reduce uncertainty in the classification of especially challenging for cytogeneticists due to complex renal tumors and may be a useful ancillary study in clini- rearrangements and less than optimal banding patterns. cal practice. Given the clinical relevance of accurately classifying patients for prognostic implications and therapeutic deci- Materials and methods sions, there is a need for diagnostic tools that reliably Tissue samples detect and quantify genetic lesions that are diagnostic for Fifty tumors with classic morphology from the four most each subgroup of renal epithelial neoplasms. common renal cell tumor subtypes (Clear Cell n = 21, Papillary n = 9, Chromophobe n = 9 and Oncocytoma n Several techniques have been utilized for genome-wide = 11) were used as a reference cohort to establish common scanning of chromosomal aberrations in renal tumors, profiles for each group (Classic Morphology Cohort). Ref- Page 2 of 13 (page number not for citation
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