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Genome-Wide Expression Profiling Reveals New Insights Into Pathogenesis and Progression of Testicular Germ Cell Tumors

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Genome-Wide Expression Profiling Reveals New Insights Into Pathogenesis and Progression of Testicular Germ Cell Tumors CANCER GENOMICS & PROTEOMICS 4: 359-368 (2007) Genome-wide Expression Profiling Reveals New Insights into Pathogenesis and Progression of Testicular Germ Cell Tumors KATHARINA BIERMANN1*, LUKAS CARL HEUKAMP1*, KLAUS STEGER2, HUI ZHOU1, FOLKER ERNST FRANKE3, VIOLETTA SONNACK2, RALPH BREHM4, JOHANNES BERG5, PATRICK JAN BASTIAN6, STEFAN CAJETAN MÜLLER6, LIHUA WANG-ECKERT7 and REINHARD BUETTNER1 1Department of Pathology and 6Department of Urology, University of Bonn; 2Department of Urology and Pediatric Urology; 3Department of Pathology, and 4Institute of Veterinary-Anatomy, -Histology and -Embryology, University of Giessen; 5Institute of Theoretical Physics, University of Cologne; 7Laboratory for Experimental Psychiatry, Life & Brain Center, Bonn, Germany Abstract. Testicular germ cell tumors (GCT) are the most genetic pathways driving the transition to seminomas and frequent malignancy in young adults and arise from embryonal carcinomas from their respective precursor lesions. intratubular germ cell neoplasia undetermined (IGCNU, also referred to as carcinoma in situ, CIS). To determine the The incidence of testicular germ cell tumors (GCT) is transcriptional programs involved in the transition from steadily increasing all over the world (6-11 per 100,000) (1, normal germ cells to GCT, and to further elucidate genetic 2). In general, GCT is suggested to be a part of the testicular differences between seminomas and non-seminomatous GCT dysgenesis syndrome, which includes cryptorchidism and the global expression profile of 12 neoplastic and 3 normal testicular atrophy (3). First described by Skakkebaek in 1972, testicular tissues were investigated by whole genome cDNA intratubular germ cell neoplasia undetermined, also referred microarrays. Transcriptional differences between seminomas to as carcinoma in situ or testicular intratubular neoplasia and embryonal carcinomas were determined and gene (IGCNU, CIS, TIN) is the common precursor lesion of all signatures characterizing histological subtypes of GCT were GCT except spermatocytic seminoma (4, 5). The current identified. The most significant difference between seminomas hypothesis of IGCNU development is that delayed or and embryonal carcinomas was the expression of compromised maturation of fetal germ epithelia leads to the spermatogenesis-associated genes (PRAME, MAGEA4, persistence of totipotent undifferentiated germ cells which SPAG1, HPX) in seminomas and regulatory genes DNMT3B undergo malignant transformation at some later stage, and SOX2 as well as small molecular weight keratins KRT8, probably during puberty (6). The precise nature of the KRT18 in embryonal carcinomas. The expression of several molecular events underlying this transformation and further selected genes (CK18, MAGE-A4, SOX2, DNMT3B, CD30, progression into either seminomas or non-seminomas KIT) was studied by immunohistochemistry or reverse remains largely unknown. Furthermore, the relationship of transcriptase-polymerase chain reaction (RT-PCR) in a large seminomas and non-seminomas is still a matter of debate collective of GCT. In summary, our data identified tumor type- and it has been hypothesized that IGCNU as well as specific gene signatures of GCT and provided new insights into seminomas may give rise to non-seminomatous tumors (7). The concept of pluripotency of IGCNU and embryonal carcinomas has been substantiated by recent gene expression studies that showed similarity to embryonic stem cells (ES), *Both authors contributed equally to the work. which also explains the histological variety of overt non- seminomatous GCT (8, 9). To elucidate molecular Correspondence to: Katharina Biermann, Department of Pathology, differences between seminomas and non-seminomas and University Hospital Bonn, Sigmund-Freud-Strasse 25, D-53127 between different subtypes of GCT we explored and Bonn, Germany. Tel: 022828719245, Fax: 022828715030, e-mail: compared transcriptional profiles of seminomas and [email protected] embryonal carcinomas by cDNA microarrays covering the Key Words: Testicular, cancer, germ, seminoma, embryonal entire human transcriptome. The gene expression of several carcinoma. genes detected by microarray analysis was studied by 1109-6535/2007 $2.00+.40 359 CANCER GENOMICS & PROTEOMICS 4: 359-368 (2007) immunohistochemistry and reverse transcriptase-polymerase http://www.pantherdb.org/. The 60-mer probes were synthesized chain reaction (RT-PCR). using standard phosphoramidite chemistry and solid-phase synthesis and quality controlled by mass spectrometry. The probes were Materials and Methods covalently bound to a nylon-derivatised substrate carried on a glass slide. Internal control probes were co-spotted at every feature (11). Probe preparation, hybridization, image generation and analysis Testicular tissues. All fresh testicular tissue samples used for were done according to the manufacturer’s guidelines for the microarray analysis were obtained immediately after orchiectomy. AB1700 Microarray system. Briefly, digoxigenin-11-uridine-5’- The use of the tissue for scientific purposes was approved by the triphosphate (Roche Diagnostics, Mannheim, Germany) labeled institutional Regional Committee for Ethics. From patients with cRNA was generated and linearly amplified from 2 Ìg of total RNA overt germ cell tumors, tumor samples and, if possible, using rt-IVT- Kit v 2.0 (Applied Biosystems). Array hybridization macroscopically normal testicular tissue were excised, snap-frozen and chemiluminescence detection were performed using an Applied and stored at –80ÆC for RNA-extraction. Several adjacent samples Biosystems Chemiluminescence Detection Kit. Briefly, 16 Ìg of were routinely fixed over-night in 4% phosphate buffered formalin at digoxigenin-labeled cRNA were fragmented into 100-400 bp room temperature and processed in paraffin wax. H&E and fragments by incubation in fragmentation buffer at 60ÆC for 30 min immunohistochemical staining with placental alkaline phosphatase and hybridized to a pre-hybridized microarray in a 1.5 ml volume at (PLAP) antibody were performed on all frozen and paraffin- 55ÆC for 16 h together with an internal control target, a 24-mer embedded tissue samples. All the tumors were classified according to oligonucleotide labeled with a fluorescent dye. After several the WHO classification of tumors based on their histology and the washing steps, chemiluminescent visualization was achieved by size of tumor or IGCNU was determined. Altogether, 29 frozen incubating the microarray with an anti-digoxigenin alkaline individual testicular tissues were used for microarray studies and RT- phosphatase conjugate (Roche Diagnostics). Per array, a total of 8 PCR, and 66 paraffin-embedded tissues for immunohistochemistry images including 2 chemiluminescent images at 5 sec and 25 sec (see below). exposures for gene expression analysis, 2 fluorescent images for feature localization and spot normalization were created. Tissue array preparation from testicular tissues. Tissue arrays were Autogridding, basic quality control, feature extraction, background constructed from formalin-fixed, paraffin embedded tissue using a correction and spot and spatial normalization were performed with Tissue Arrayer (Beecher Instruments, Silver Springs, MD, USA) the Applied Biosystems 1700 Chemiluminescent Microarray by obtaining single 1.2 mm cores from each paraffin block and their Analyzer according to the manufacturer’s instructions. Based on our placement in predrilled slots of the recipient block as previously experience and published data (12), extremely small variation described (10). The array included 132 testicular tissue cores from between technical replicates on the AB1700 platform and in the 66 individuals. Among them 10 normal testis, 6 IGCNU, 30 light of limited resources one array per sample was hybridized and seminomas and 20 embryonal carcinomas. Immunohistochemistry biological rather than technical replicates performed. for the proteins KIT, MAGE-A4, CK18 and CD30 was performed on the tissue arrays. Bioinformatic data processing and analysis. All probe sets flagged as RNA preparation. Prior to RNA extraction, serial sections were bad spots by the AB1700 software (FLAG >5000) were removed taken to ensure sample purity and the amount of target tissue and samples with more than 50% missing values were excluded estimated in the first and last section by standard H&E stain. The from analysis. Remaining missing values were replaced with average total RNA was extracted from normal testis (n=5), IGCNU signals from replicate arrays within the same subgroup. The data (n=11), seminomas (n=5), embryonal carcinomas (n=3), were normalized by quantile normalization and transformed to log2 teratomas (n=2) and teratocarcinomas (n=3). The RNA was scale, using Bioconducter (http://www.bioconductor.org/docs/faq/) extracted with Trizol (Invitrogen, Karlsruhe, Germany) or RNeasy R software and the AB1700 Data Analysis script (Yongming Extraction Kit according to the manufacturer’s protocol (Qiagen, Andrew Sun, Applied Biosystems). Hilden, Germany). The RNA quality was assessed with a Agilent Bioanalyzer 2000 (Agilent Technologies, Palo Alto, CA, USA) and Real-time PCR. Real-time QPCR was performed on cDNA only samples with a RNA integrity (RIN) value >8 were used for synthesized from 1 Ìg of RNA using nonamer primers and an further analysis. Omniscript Synthesis Kit (Qiagen). The intron-spanning primer pairs were designed by Applied Biosystems (assay ID Whole genome gene expression array
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