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New Insights Into Testicular Germ Cell Tumorigenesis from Gene Expression Profiling1

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New Insights Into Testicular Germ Cell Tumorigenesis from Gene Expression Profiling1 [CANCER RESEARCH 62, 2359–2364, April 15, 2002] New Insights into Testicular Germ Cell Tumorigenesis from Gene Expression Profiling1 Rolf I. Skotheim, Outi Monni, Spyro Mousses, Sophie D. Fosså, Olli-P. Kallioniemi, Ragnhild A. Lothe,2 and Anne Kallioniemi Department of Genetics, Institute for Cancer Research [R. I. S., R. A. L.] and Department for Oncology and Radiotherapy [S. D. F.], The Norwegian Radium Hospital, N-0310 Oslo, Norway; Biomedicum Biochip Center, Biomedicum Helsinki, FIN-00290 Helsinki, Finland [O. M.]; Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892 [O. M., S. M., O-P. K., A. K.]; and Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33520 Tampere, Finland [A. K.] ABSTRACT teristic of virtually all TGCTs (4, 5). In addition, specific gains and losses from several other chromosomal regions have been described. 3 We have shown recently that about half of the human TGCTs reveal Although molecular studies have shown some genes to be altered at DNA copy number increases affecting two distinct regions on chromosome the DNA and/or expression levels in a limited number of TGCTs, the arm 17q. To identify potential target genes with elevated expressions attributable to the extra copies, we constructed a cDNA microarray target genes reflecting the nonrandom chromosomal aberrations re- containing 636 genes and expressed sequence tags from chromosome 17. main unknown (for a review of TGCT genetics, see Refs. 6 and 7). The expression patterns of 14 TGCTs, 1 carcinoma in situ, and 3 normal We have demonstrated recently by a genome-wide copy number testis samples were examined, all with known chromosome 17 copy num- analysis using CGH that sequences on chromosome arm 17q are bers. The growth factor receptor-bound protein 7 (GRB7) and junction frequently overrepresented in TGCTs, and two common regions of plakoglobin (JUP) were the two most highly overexpressed genes in the copy number increase were identified (8). Gain of the proximal TGCTs. GRB7 is tightly linked to ERBB2 and is coamplified and coex- region, 17q11–q21, is preferentially observed in nonseminomas, pressed with this gene in several cancer types. Interestingly, the expression whereas gain of the distal region, 17q24–qter, is common to all levels of ERBB2 were not elevated in the TGCTs, suggesting that GRB7 TGCTs (8). Nonrandom gain at 17q has also been reported in several might be the target for the increased DNA copy number in TGCTs. other cancer types (9–13). Because of the limited knowledge of altered gene expression in the devel- opment of TGCTs, we also examined the expression levels of 512 addi- To identify differentially expressed genes on chromosome 17 in tional genes located throughout the genome. Several genes novel to tes- TGCTs, we analyzed a series of TGCTs and normal testicular samples ticular tumorigenesis were consistently up- or down-regulated, including using a custom-made cDNA microarray with a comprehensive chro- POV1, MYCL1, MYBL2, MXI1, and DNMT2. Additionally, overexpression mosome 17 coverage (14). All analyzed tumors had been studied of the proto-oncogenes CCND2 and MYCN were confirmed from the previously by CGH, and thus, the expression profiles could be related literature. The overexpressions were for some of the target genes closely to the DNA copy numbers. The expression levels of 512 additional associated to either seminoma or nonseminoma TGCTs, and hierarchical genes mapping elsewhere in the genome, including many cancer- cluster analysis of the gene expression data effectively distinguished related genes, were also analyzed in the same set of TGCT samples. among the known histological subtypes. In summary, this focused func- tional genomic characterization of TGCTs has lead to the identification of new gene targets associated with a common genomic rearrangement as MATERIALS AND METHODS well as other genes with potential importance to testicular tumorigenesis. Tumor and Cell Line Samples. Eighteen testicular tissue samples were analyzed, including 8 pure seminomas, 6 nonseminomas, 1 carcinoma in situ INTRODUCTION (from the vicinity of a nonseminoma), and 3 normal samples. The tumors were selected from a series of primary TGCTs analyzed previously by CGH (8). TGCT3 is the most common malignancy among adolescent and Four of the 8 seminomas had gains at distal 17q, including the 17q24–qter young adult Caucasian males, and the incidence has been steadily region (Fig. 1A). The 6 nonseminomas (4 embryonal carcinomas and 2 im- increasing over the past 50 years (1, 2). TGCTs are classified into two mature teratomas) had large gains at chromosome 17, all including the 17q11– main histological subtypes, seminomas and nonseminomas, and there q21 region. The use of these samples in cDNA microarray experiments was are two models describing their development from carcinomas in situ approved by the Regional Committee for Medical Research Ethics in Norway and the NIH Office of Human Subjects Research. (3). Either both subtypes develop independently from carcinomas in A pool of two breast cancer cell lines, HBL100 and MDA-436 (American situ, or they develop as a continuum where seminomas may progress Type Culture Collection, Manassas, VA), was used as a common reference in further into nonseminomas. the cDNA microarray experiments. These cell lines were selected based on the TGCTs are generally in the triploid range, and isochromosome 12p facts that they show no increase in copy number at 17q and express most genes or gain of DNA sequences from chromosome arm 12p is a charac- on the cDNA microarray to some extent (10, 14). cDNA Microarray Experiments. The construction of the cDNA microar- Received 12/27/01; accepted 2/14/02. ray with comprehensive chromosome 17 coverage has been described previ- The costs of publication of this article were defrayed in part by the payment of page ously by Monni et al. (14). The microarray consisted of printed PCR products charges. This article must therefore be hereby marked advertisement in accordance with from 636 sequence-verified IMAGE cDNA clones (Research Genetics, Hunts- 18 U.S.C. Section 1734 solely to indicate this fact. ville, AL), including 201 known genes from the entire chromosome 17 and 435 1 Supported by the Research Council of Norway (to R. I. S.) and the Norwegian Cancer Society (to R. A. L.). ESTs from the 17q arm. An additional 512 sequence-verified IMAGE cDNA 2 To whom requests for reprints should be addressed, at Department of Genetics, clones were placed on the array, representing transcribed sequences located Institute for Cancer Research, The Norwegian Radium Hospital, N-0310 Oslo, Norway. elsewhere in the genome. Eighty-eight of these were housekeeping genes and Phone: 47-22934415; Fax: 47-22934440; E-mail: [email protected]. were used for calibration among the different experiments (15), 162 were a 3 The abbreviations used are: TGCT, testicular germ cell tumor; CCND2, cyclin D2; CGH, comparative genomic hybridization; DNMT2, DNA (cytosine-5)-methyltransferase 2; selection of known or putative cancer-related genes, and 262 were a collection ERBB2, v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; EST, expressed of genes and ESTs from chromosome 10. sequence tag; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GRB7, growth factor Preparation and printing of the cDNA clones on glass slides, probe prepa- receptor-bound protein 7; JUP, junction plakoglobin; LLGL2, lethal giant larvae (Drosophila) rations, hybridizations, and image generation and analyses were performed as homolog 2; MYBL2, B-Myb; MYCL1, L-Myc; MYCN, N-Myc; MXI1, MAX-interacting protein 1; PDE6G, phosphodiesterase 6G, cGMP-specific, rod, gamma; POV1, prostate cancer described (16). Briefly, mRNA was isolated from the test samples by using the overexpressed gene 1; RT-PCR, reverse transcription-PCR. Trizol reagent (Life Technologies, Inc., Rockville, MD) and oligo(dT)25 dyna- 2359 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2002 American Association for Cancer Research. GENE EXPRESSION IN TESTICULAR GERM CELL TUMORS Fig. 1. Genetic changes in testicular germ cell tumors. A, genomic copy number gains on chromo- some 17 as seen by comparative genomic hybrid- ization. Each colored bar represents gain from the corresponding chromosome segment in the tumor indicated below. B, sample tree (dendrogram) from the hierarchical cluster analysis of 18 testicular samples. Letters below the dendrogram represent the tissue sources: N, normal testis; C, carcinoma in situ; I, immature teratoma; E, embryonal carci- noma, and S, seminoma. The vertical distances on the dendrogram reflect the relatedness of neighbor- ing samples. A gene expression map with pseudo- colors coding for the normalized ratios of up- and down-regulated genes in TGCTs located on chro- mosome 17 (C) and elsewhere in the genome (D)is shown. Transcribed sequences are presented in rows, and each experiment (cDNA sample) is shown in columns. Thus, each cell in the matrix represents the expression level of a single transcript in a single sample. Numbers in parentheses behind the ESTs provide the IMAGE clone ids. E, color coding for the normalized expression ratios (ex- pression relative to the average expressions in the three normal samples). beads (Dynal Biotech, Oslo, Norway) according to the manufacturers’ speci- data were hierarchically clustered by both gene and sample sides (501 clones fications. From the
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