SNP Arrays in Cancer Diagnostics

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1 1 1. Introduction SNP Arrays in Cancer Diagnostics Federico A. Monzon, M.D. The Methodist Hospital Research Institute, Houston TX Detection of acquired chromosomal gains/losses in human tumors is clinically helpful for the confirmation of suspected diagnosis, such as 1p/19q deletions in oligodendrogliomas, chromosomal gains associated with bladder cancer in urine specimens or monitoring progression of disease in lymphomas and leukemias. Most of the methodologies in clinical use detect a specific target for deletion or amplification and thus, cannot detect multiple chromosomal copy number aberrations (CNA) with high resolution in one assay. In research, array-based technologies are being used to identify recurrent CNA changes in tumors, with prognostic or diagnostic implications.(1, 2) Array comparative genomic hybridization (acgh), is already in clinical use for the detection of constitutional CNA alterations(3) SNP Arrays. Single nucleotide polymorphism (SNP) arrays allow researchers to determine both the copy number status and the genotype of close to a million SNPs, detecting regional gains/losses and the presence of loss-of-heterozygosity (LOH) in a single assay. Thus, while SNP arrays have been primarily used for genetic association studies, they have also proven useful for studying gains and losses of genetic material in human tumors.(2, 4-7) In addition, SNP arrays have several advantages over other methods for detecting copy number changes, such as CGH, acgh, SKY, and FISH. The advantages include high resolution coverage of the entire genome, scalability and automation, ease of scoring, minimal total genomic DNA needed, stringent quality control manufacturing, relatively low cost, and ability to use frozen and paraffin embedded tissues (8-11). A significant advantage of genome-wide copy number analysis with the SNP arrays compared to targeted assays is the ability to detect common, characteristic genetic lesions common to a tumor type (diagnostic) and additional chromosomal aberrations that might define potentially specific tumor subsets (possibly prognostic). It is likely, that array-based technologies for CNA analysis will become an additional tool for cancer diagnosis in molecular diagnostics laboratories. The Affymetrix SNP mapping array platform has been rapidly increasing in density with the 10K array released in 2003 (10,000 SNP probes), to the 6.0 array in June of 2007 (~906,600 SNP probes and ~946,000 probes for the detection of copy number variation). These latest, ultra-high density arrays are remarkably powerful with several research applications. However, there are several issues that make them less attractive for developing routine clinical assays at this time, such as cost, longer turnaround-time, higher complexity protocols, limited availability and maturity of analysis software, and inter-laboratory variability for the CCN analysis applications. In our laboratory, we have found that the 10K SNP arrays provide sufficient resolution for detecting, large chromosomal aberrations of clinical significance in specific tumor types and that the 250K arrays appear to be adequate for identification of the great majority of clinically relevant chromosomal CNAs. 2. Virtual Karyotyping of Tumors

2 Renal Cancer Chromosomal lesions in Renal Cell Carcinoma Specific genetic abnormalities have been found in the different types of renal cell tumors and are summarized in Table 1 (12). Clear cell RCC shows deletions in the p arm of chromosome 3, while papillary RCC usually presents with trisomies of chromosomes 7 & 17 and/or loss of chromosome Y. Chromophobe RCC is characterized by a hypodiploid genome with monosomies of chromosomes 1, 2, 6, 10, 13, 17 and 21. Oncocytoma shows either normal chromosomes or copy number alterations in chromosome 1. Although the chromosomal lesions that characterize each subtype of renal epithelial neoplasms have been known for some time, this knowledge is not routinely used in the diagnostic evaluation of these tumors. Table 1. Frequency of classic chromosomal aberrations in renal epithelial neoplasms. Classic Type of cytogenetic Renal Tumor findings Clear Cell RCC Papillary RCC Chromophobe RCC Oncocytoma del(3)(p): 3p14, 3p21, 3p25-26 Trisomy 7 and 17 % Cases with chromosomal abnormality n Platform Comment Ref 81 % 26 acgh (13) 98% 118 CG (14) 98% 52 LOH (15) 100% 11 FISH (16) 67%/43% 19/20 FISH Low / High Grade (17) 100% 6 FISH (16) 100%/38% 9/16 CGH Type 1 / Type 2 (18) 100% 4 acgh (13) 95% 10 LOH (15) Loss of 1, 2, 6, 10, 13, 17 and/or 21 74% 19 FISH (19) Chr 1 loss or normal 100% 10 FISH (19) Array CGH has been used to accurately classify RCCs by histologic type, based on the specific genetic alterations described above (13, 20). However, most studies have been descriptive and have not attempted to develop and validate a molecular diagnostic tool Molecular Diagnosis of Renal Cell Carcinoma More than a decade ago, Steiner and Sidransky proposed the use of loss of heterozygosity (LOH) analysis with microsatellites to detect specific chromosomal deletions in renal tumors (21). However, these assays have not been incorporated into routine clinical practice, most likely because in order to comprehensively detect all abnormalities, more than 12 microsatellite loci would need to be evaluated (at least 3 for each chromosomal region) in order to obtain clinically acceptable sensitivity and specificity. In addition, this technique does not detect chromosomal gains and therefore chromosomal anomalies characteristic of papillary RCC and other lesions with possible prognostic value would not be detected. Other ancillary studies, such as conventional

3 3 cytogenetic analysis, and fluorescent in situ hybridization (FISH) panels, have been used to aid in classification and prognostic stratification with limited success. It has been reported that FISH on 5um sections of paraffin embedded tissue can underestimate chromosomal anomalies when compared to analysis of entire nuclei (22, 23). Furthermore, FISH can only provide targeted copy number information (and would miss gene conversion events resulting in copy neutral LOH ). Recent publications have reported that copy neutral LOH constitutes 50-80% of the LOH in human cancers. (7, 24-26). Thus, there is a need for new diagnostic techniques that can reliably and costeffectively identify genomic abnormalities in renal cell tumors Virtual Karyotyping for Diagnosis of Renal Cell Carcinoma We have shown that SNP arrays can reliably detect chromosome copy number aberrations and LOH in paraffin embedded tissues with the use of an optimized protocol(10). We then applied this technology to 20 cases of renal cell tumors with four different morphologic subtypes (clear cell, papillary and chromophobe carcinomas and oncocytoma)(11). Copy number aberrations and LOH detected by the SNP arrays were in agreement with the genetic abnormalities described in the literature for the different types of renal epithelial tumors (12). These characteristic patterns of chromosomal aberrations permit classification of each sample based on the presence of 3p deletions in clear cell renal cell carcinoma, trisomy 7 & 17 in papillary renal cell carcinoma, losses of chromosomes 1, 2, 6, 10, 13 and 17 in chromophobe renal cell carcinoma and monosomy 1, no aberrations or chromosome 19 aberrations in oncocytomas. One case of papillary carcinoma with type 2 histology did not show the characteristic trisomy 7/17 for this group. It has been previously demonstrated that these chromosomal aberrations are much less frequent in papillary type 2 tumors and thus this result is not entirely unexpected (18). It is important to note that the detection of copy number aberrations in tumors can be complicated by the presence of normal tissue (normal contamination), which can lead to false negatives. The ability to macrodissect tissue from a paraffin embedded section permitted us to minimize normal tissue contamination. In addition to those expected in the specific tumor type, we identified additional non-characteristic chromosomal abnormalities in almost all cases or renal cell carcinoma. Most of the additional chromosomal abnormalities found are in agreement with published findings and some have been associated with aggressive behavior or progression (13, 14, 27). Additional copy number aberrations are quite frequent and some of these lesions seem to define specific subsets of tumors (e.g. clear cell carcinoma with -9p)(27). To explore the use of this technique in the diagnostic workup of morphologically challenging renal tumors, we analyzed three cases where the final classification after routine pathology was not definitive (renal cell carcinoma, unclassified). Two of the cases consisted of eosinophilic neoplasms with features of chromophobe carcinoma along with features of oncocytoma. These cases illustrate a common differential diagnosis between oncocytoma and eosinophilic variant of chromophobe renal cell carcinoma. This situation is of particular importance, since it involves the distinction between a malignant neoplasm (albeit with good prognosis) and a benign tumor, with significant medical and psychological implications. Immunohistochemistry is of limited utility in this situation, since staining patterns for these two neoplasms are quite similar.(28) Our results show that the 10K 2.0 SNP array results can reliably distinguish between oncocytoma and chromophobe renal cell carcinoma in a single assay with DNA obtained from formalin-fixed paraffin embedded tissue.

4 4 In the third case, the consideration is of a tumor with mixed papillary architecture and clear cell morphology with granular features in a patient with multiple bona-fide clear cell and papillary tumors. This is a complex case where the differential diagnosis includes clear cell, papillary and chromophobe renal cell carcinoma. The diagnosis of mixed tumors (renal cell carcinoma, unclassified) is not an uncommon situation, which has implications in prognosis and therapeutic decisions. In this case, positive RCC antigen and CD10 suggest that this tumor could be of clear cell origin but the CK7, BerEp4 and colloidal iron positivity, along with the morphologic features precluded the pathologist from issuing a definitive classification, since these are features of papillary and chromophobe carcinomas. The chromosome copy number analysis with SNP array clearly identified chromosomal loss at 3p and confirms that this tumor is a clear cell renal cell carcinoma. These real-life examples are indicative of how this assay could be incorporated in everyday clinical practice for the pathologic evaluation of renal epithelial neoplasms Malignant Gliomas Although the diagnosis of malignant glial tumors is usually done on light microscopic evaluation, it is now well established that molecular alterations are characteristic of some of the subtypes of malignant glial tumors (30). For example, the presence of 1p/19q co-deletion differentiates oligodendendrogliomas (OD) from astrocytomas (AS) and that it is a powerful predictor of response to chemotherapy and longer survival. Loss of 1p predicts response to chemotherapy with PCV (procarbazine, CCNU, and vincristine) and seems to also predict response to temozolamide. Other chromosomal aberrations in other glioma subgroups (such as anaplastic and grade II oligodendrogliomas) can be predictive of chemotherapy resistance and/or aggressive behavior (such as EGFR amplification). Evaluation of 1p/19q loss is now routine for complex cases in which oligodendroglioma is part of the differential diagnosis, and some people suggest that it should be done on every glioma case. In most places, this test is performed by the use of FISH or LOH with microsatellites. As discussed above, using any of these techniques implicates the necessity of doing multiple assays for each of the chromosomal aberrations being evaluated. Virtual Karyotyping with SNP microarrays could potentially be used to identify simultaneously lesions involving 1p, 19q and the EGFR locus. 3. Conclusions Although it is common for ancillary studies to have subjective interpretations rendered by experienced pathologist and technicians, the results from the chromosome copy number analysis with SNP arrays are easy to interpret. Furthermore, the output can be readily related to a conventional karyotype, so clinicians and pathologists are already familiar with chromosome copy number information and its meaning. However, it is imperative that the interpretation of virtual karyotypes be performed along with clinical history, morphology and other studies. It is important to mention, that in order for this technology to become the basis of a clinically accepted test, it will be necessary to perform validation studies with large patient cohorts that adequately represent the frequency of the characteristic chromosomal aberrations in each diagnostic group where this test need to be used. Also, correlation with outcome data will be paramount for understanding the diagnostic, prognostic and therapeutic implication of genomic changes in tumors.

5 5 In summary, our results show that chromosome copy number changes detected by SNP arrays can produce information that a pathologist can use to reliably classify renal tumors into the four most common diagnostic entities. Furthermore, we have applied this technique to a limited number of morphologically challenging cases that could not be resolved by routine pathology but showed characteristic chromosomal abnormalities that would allow classification. Also, there is potential to use this approach with other tumors with characteristics chromosomal aberrations such as malignant glial tumors. 4. References 1. Kim T-M, Yim S-H, Lee J-S, et al. Genome-Wide Screening of Genomic Alterations and Their Clinicopathologic Implications in Non-Small Cell Lung Cancers. Clin Cancer Res 2005; 11: Zhou X, Mok SC, Chen Z, Li Y, Wong DT. Concurrent analysis of loss of heterozygosity (LOH) and copy number abnormality (CNA) for oral premalignancy progression using the Affymetrix 10K SNP mapping array. Hum Genet 2004; 115: Bejjani BA, Theisen AP, Ballif BC, Shaffer LG. Array-based comparative genomic hybridization in clinical diagnosis. Expert Rev Mol Diagn 2005; 5: Bignell GR, Huang J, Greshock J, et al. High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res 2004; 14: Lindblad-Toh K, Tanenbaum DM, Daly MJ, et al. Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nat Biotechnol 2000; 18: Herr A, Grutzmann R, Matthaei A, et al. High-resolution analysis of chromosomal imbalances using the Affymetrix 10K SNP genotyping chip. Genomics 2005; 85: Huang J, Wei W, Zhang J, et al. Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum Genomics 2004; 1: Nannya Y, Sanada M, Nakazaki K, et al. A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res 2005; 65: Zhou X, Rao NP, Cole SW, et al. Progress in concurrent analysis of loss of heterozygosity and comparative genomic hybridization utilizing high density single nucleotide polymorphism arrays. Cancer Genet Cytogenet 2005; 159: 53-7.

6 6 10. Lyons-Weiler M, Hagenkord J, Sciulli CM, Dhir R, Monzon FA. Optimization of the Affymetrix GeneChip mapping 10K 2.0 assay for routine clinical use on formalin fixed paraffin embedded tissues. Diagnostic Molecular Pathology 2008; 17: Monzon FA, Hagenkord J, Lyons-Weiler M, et al. Whole Genome SNP Arrays as a Diagnostic Tool for Detection of Chromosomal Aberrations in Renal Tumors. Modern Pathology 2008; 17: van den Berg E, Storkelvan S. Kidney: Renal Cell Carcinoma. Atlas Genet Cytogenet Oncol Haematol; Yoshimoto T, Matsuura K, Karnan S, et al. High-resolution analysis of DNA copy number alterations and gene expression in renal clear cell carcinoma. J Pathol 2007; 213: Gunawan B, Huber W, Holtrup M, et al. Prognostic Impacts of Cytogenetic Findings in Clear Cell Renal Cell Carcinoma: Gain of 5q31-qter Predicts a Distinct Clinical Phenotype with Favorable Prognosis. Cancer Research 2001; 61: Bugert P, Kovacs G. Molecular differential diagnosis of renal cell carcinomas by microsatellite analysis. Am J Pathol 1996; 149: Receveur AO, Couturier J, Molinie V, et al. Characterization of quantitative chromosomal abnormalities in renal cell carcinomas by interphase four-color fluorescence in situ hybridization. Cancer Genet Cytogenet 2005; 158: Lager DJ, Huston BJ, Timmerman TG, Bonsib SM. Papillary renal tumors. Morphologic, cytochemical, and genotypic features. Cancer 1995; 76: Jiang F, Richter J, Schraml P, et al. Chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes. Am J Pathol 1998; 153: Brunelli M, Eble JN, Zhang S, et al. Eosinophilic and classic chromophobe renal cell carcinomas have similar frequent losses of multiple chromosomes from among chromosomes 1, 2, 6, 10, and 17, and this pattern of genetic abnormality is not present in renal oncocytoma. Mod Pathol 2005; 18: Wilhelm M, Veltman JA, Olshen AB, et al. Array-based comparative genomic hybridization for the differential diagnosis of renal cell cancer. Cancer Res 2002; 62: Steiner G, Sidransky D. Molecular differential diagnosis of renal carcinoma: from microscopes to microsatellites. Am J Pathol 1996; 149:

7 7 22. Aubele M, Zitzelsberger H, Szücs S, et al. Comparative FISH analysis of numerical chromosome 7 abnormalities in 5-µm and 15-µm paraffin-embedded tissue sections from prostatic carcinoma. Histochem Cell Biol 1997; 107: El-Naggar AK, van Dekken HD, Ensign LG, Pathak S. Interphase cytogenetics in paraffin-embedded sections from renal cortical neoplasms : Correlation with cytogenetic and flow cytometric DNA ploidy analyses. Cancer Genet Cytogenet 1994; 73: Beroukhim R, Lin M, Park Y, et al. Inferring loss-of-heterozygosity from unpaired tumors using high-density oligonucleotide SNP arrays. PLoS Comput Biol 2006; 2: e Ishikawa S, Komura D, Tsuji S, et al. Allelic dosage analysis with genotyping microarrays. Biochemical and biophysical research communications 2005; 333: Kloth JN, Oosting J, van Wezel T, et al. Combined array-comparative genomic hybridization and single-nucleotide polymorphism-loss of heterozygosity analysis reveals complex genetic alterations in cervical cancer. BMC genomics 2007; 8: Brunelli M, Eccher A, Gobbo S, et al. Loss of chromosome 9p is an independent prognostic factor in patients with clear cell renal cell carcinoma. Mod Pathol 2008; 21: Balani JP, Catroppo JF, McHale T, et al. Immunohistochemical profile of renal epithelial neoplasms: an institutional experience with 92 consecutive cases. Mod Pathol 2006; 19: 129A. 29. Brunelli M, Eble JN, Zhang S, et al. Eosinophilic and classic chromophobe renal cell carcinomas have similar frequent losses of multiple chromosomes from among chromosomes 1, 2, 6, 10, and 17, and this pattern of genetic abnormality is not present in renal oncocytoma. Mod Pathol 2005; 18: Louis DN. MOLECULAR PATHOLOGY OF MALIGNANT GLIOMAS. Annual Review of Pathology: Mechanisms of Disease 2006; 1:

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