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Amplification and Overexpression of the Dual-Specificity Tyrosine-(Y)- Phosphorylation Regulated Kinase 2 (DYRK2) Gene in Esophageal and Lung Adenocarcinomas1

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Amplification and Overexpression of the Dual-Specificity Tyrosine-(Y)- Phosphorylation Regulated Kinase 2 (DYRK2) Gene in Esophageal and Lung Adenocarcinomas1 [CANCER RESEARCH 63, 4136–4143, July 15, 2003] Amplification and Overexpression of the Dual-Specificity Tyrosine-(Y)- Phosphorylation Regulated Kinase 2 (DYRK2) Gene in Esophageal and Lung Adenocarcinomas1 Charles T. Miller, Sanjeev Aggarwal, Theodore K. Lin, Susan L. Dagenais, Jorge I. Contreras, Mark B. Orringer, Thomas W. Glover, David G. Beer, and Lin Lin2 Departments of Surgery, Section of Thoracic Surgery [C. T. M., S. A., T. K. L., J. I. C., M. B. O., D. G. B., L. L.] and Human Genetics [S. L. D., T. W. G.], University of Michigan Medical School, Ann Arbor, Michigan 48109 ABSTRACT fied previously a novel amplicon at 8p22–23 in gastroesophageal adenocarcinomas (8). Using the STS3-amplification mapping ap- Genomic amplification can lead to the activation of cellular proto- proach, the core-amplified domain was narrowed to include the cys- oncogenes during tumorigenesis, and is observed in most, if not all, human teine protease gene CTSB and the transcription factor GATA-4 (8, 9). malignancies, including adenocarcinomas of lung and esophagus. Using a two-dimensional restriction landmark genomic scanning technique, we Similarly, we identified and characterized an amplicon at 19q12 and identified five NotI/HinfI fragments with increased genomic dosage in an revealed cyclin E as the best candidate gene selected by the 19q12 adenocarcinoma of the gastroesophageal junction. Four of these amplified amplification in gastroesophageal adenocarcinomas (10). In addition fragments were matched within three contigs of chromosome 12 using the to oncogene activation via gene amplification, inactivation of the bioinformatics tool, Virtual Genome Scan. All three of the contigs map to tumor suppressor gene p53 occurs frequently in esophageal adenocar- the 12q13-q14 region, and the regional amplification in the tumor was cinoma (Ͼ87%) and early in low- and high-grade Barrett’s dysplasia verified using comparative genomic hybridization analysis. The 12q14 (11, 12). Amplification and overexpression of the MDM2 oncogene amplicon was characterized using sequence tagged site-amplification were reported in sarcomas lacking detectable p53 alterations, indicat- mapping with DNA from paired normal-tumor tissues of 75 gastroesoph- ing the role of coordinately abrogating the suppression of cell growth ageal and 37 lung adenocarcinomas. The amplicon spans a region of >12 regulated by the p53 pathway (13, 14). Whereas involvement of p53 Mb between genes DGKA and BLOV1. The core-amplified domain was determined to be <0.5 Mb between marker WI-12457 and gene IFNG. was observed frequently in esophageal adenocarcinomas, amplifica- However, MDM2, a well-documented oncogene of the region, is outside the tion of the MDM2 gene was not detected in one study (15) and was core-domain. Eleven genes and expressed sequence tags within the ampli- reported infrequently (4%) in another study in this type of tumor (16). con were selected for quantitative reverse transcription-PCR, and DYRK2, Using CGH, Moskaluk et al. (17) and van Dekken et al. (18) reported a member of the dual-specificity kinase family, was overexpressed in all of increased 12q DNA copy number in 27% and 39% of esophageal the tumors showing gene amplification. Among the sequence tagged site/ adenocarcinomas. However, these regions of gain were mapped to expressed sequence tag/gene markers tested, DYRK2 demonstrated the 12q21-q24, suggesting an additional 12q amplicon because MDM2 is highest DNA copy number and the highest level of mRNA overexpression mapped to the 12q13–15 region (13, 19). Tumors with amplified in the tumors. Moreover, DYRK2 mRNA overexpression (>2.5-fold of genes closely linked to MDM2 but without MDM2 amplification or normal mean) was found in 18.6% of additional 86 lung adenocarcinomas with discontinuous amplicons including MDM2 were also reported in an assay using oligonucleotide microarrays. DYRK2 mRNA overexpres- sion occurs more frequently than gene amplification in both esophageal (20–22). To clarify the amplification status within the 12q region, the and lung adenocarcinomas. This is the first report of amplification and current investigation was undertaken using RLGS (23, 24) combined overexpression of DYRK2 in any tumor type. with a recently developed bioinformatics tool, VGS (25). Use of these tools allows individual genomic fragments amplified in a tumor genome to be identified. DYRK2, a dual-specificity tyrosine-(Y)- INTRODUCTION phosphorylation regulated kinase gene, was identified as the most The incidence of esophageal adenocarcinoma has rapidly increased frequently amplified and overexpressed gene among the STS/EST/ in many western countries including the United States, the United gene markers examined, and also demonstrated the highest mRNA Kingdom, the Netherlands, Denmark, and Australia over the past 3 overexpression level among the genes tested in this series of gastroe- decades (1, 2). A poor overall 5-year survival rate of Ͻ10% portends sophageal and lung adenocarcinomas. Both lung and esophageal ad- the future clinical importance of this disease (3). Invasive adenocar- enocarcinomas were examined in this study to determine whether the cinoma is accompanied frequently with Barrett’s metaplasia, an in- amplicon is tumor type-specific or whether it occurs in multiple tumor testinalized columnar epithelium that replaces the normal squamous types. The present study represents the first complete characterization epithelium at the distal esophagus as a result of chronic gastroesoph- of the 12q14 amplification in both lung and esophageal adenocarci- ageal reflux (4, 5). Smoking and obesity have been implicated as nomas, and is the first to report amplification and overexpression of additional risk factors for the disease (6, 7). DYRK2 in any human cancer. Amplification of dominant-acting oncogenes plays a significant role in the development and/or progression of many types of human MATERIALS AND METHODS cancer, including esophageal and lung adenocarcinomas. We identi- Tissue Collection. After obtaining written consent, 75 esophageal and Received 12/4/02; accepted 5/7/03. gastric cardia adenocarcinomas, the corresponding normal squamous esopha- The costs of publication of this article were defrayed in part by the payment of page gus or gastric mucosa, and 123 lung adenocarcinomas were obtained from charges. This article must therefore be hereby marked advertisement in accordance with patients undergoing esophagectomy or pulmonary resection at the University 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by National Cancer Institute Grant CA71606 and the Weber Research Fund. Supported also by NIH Training Grant CA009672-08 (to S. A.). 3 The abbreviations used are: STS, sequence tagged site; RLGS, restriction landmark 2 To whom requests for reprints should be addressed, at MS RB II B560, Box 0686, genome scanning; VGS, Virtual Genome Scan; CGH, comparative genomic hybridiza- Department of Surgery, Section of General Thoracic Surgery, University of Michigan tion; QG-PCR, quantitative genomic-PCR; EST, expressed sequence tag; NCBI, National Medical School, Ann Arbor, MI 48109. Phone: (734) 647-2787; Fax: (734) 763-0323; Center for Biotechnology Information; RT-PCR, reverse transcription-PCR; GAPDH, E-mail: [email protected]. glyceraldehyde-3-phosphate dehydrogenase. 4136 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2003 American Association for Cancer Research. DYRK2 GENE AMPLIFICATION IN ESOPHAGEAL ADENOCARCINOMAS Fig. 1. Two-dimensional RLGS analysis of NotI/HinfI DNA fragments from the normal and tumor tissues of patient E13, and a VGS image of virtual NotI/HinfI fragments of chromosome 12. DNA fragments from a gastroesophageal adenocar- cinoma of patient E13 (B) and normal tissue from the same patient (A) were resolved on two-dimen- sional gels. As shown, the comparison of relative intensity of each fragment (spot) between normal (A) and tumor (B) reveals five such fragments, B1 through B5 (arrows in B), that are darker in tumor as compared with corresponding spots A1 through A5 (arrows in A) in normal, suggesting increased DNA copy number in each of the five fragments in the tumor. C, matched virtual fragments C1 through C4 (black dots indicated by arrows in C) are shown on a VGS image with NotI/HinfI frag- ments from chromosome 12 (white dots in C). Fragment C5 was not found with any chromosomes using the VGS tool analysis, indicating the possible unavailability of sequences for this fragment in the GenBank databases. of Michigan Medical Center between 1992 and 2000. Patients in this study had for quantitative genomic PCR as described previously (9). PCR primers were no preoperative radiotherapy or chemotherapy. A small portion of each tissue designed to assure that the melting temperature (Tm) of each primer set was was embedded in OCT compound (Miles Scientific, Naperville, IL) and stored compatible with that of the internal control, herein GAPDH, which resides on Ϫ Ϫ at 70°C; the remainder was stored at 70°C until use. the same chromosome 12 so the ratio of tumorsample/GAPDH: normalsample/GAPDH DNA Isolation and RLGS-combined VGS Analyses. High molecular will reflect the actual DNA copy numbers increased in tumor. The quantity of weight DNA was extracted as described previously (26) from tumors with the normal and tumor genomic DNA was measured by fluorometry (TKO100; Ͼ70% tumor cellularity. Two-dimensional RLGS was performed as described Hoefer Scientific Instruments, San Francisco, CA) to ensure equity of the previously
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