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Amplification of MDS1/EVI1 and EVI1, Located in the 3q26.2 Amplicon, Is Associated with Favorable Patient Prognosis in Ovarian Cancer

Departments of ¹ Molecular Therapeutics, ² Pathology, and ³ Gynecologic Oncology, M. D. Anderson Cancer Center, University of Texas, Houston, Texas; ⁴ Department of Laboratory Medicine, University of California, San Francisco, and the Lawrence Berkeley National Laboratory, Berkeley, California; ⁵ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California; and ⁶ New York University, New York, New York

Requests for reprints: Meera Nanjundan, M. D. Anderson Cancer Center, Department of Molecular Therapeutics, University of Texas, 1515 Holcombe Boulevard, Box 0950, Houston, TX 77054. Phone: 713-563-4225; Fax: 713-563-4235; E-mail: mnanjund{at}mdanderson.org.

Increased copy number involving chromosome 3q26 is a frequent and early event in cancers of the ovary, lung, head and neck, cervix, and BRCA1 positive and basal breast cancers. The p110 catalytic subunit of phosphoinositide-3-kinase (PI3KCA) and protein kinase C (PKC) have previously been shown as functionally deregulated by 3q copy number increase. High-resolution array comparative genomic hybridization of 235 high-grade serous epithelial ovarian cancers using contiguous bacterial artificial chromosomes across 3q26 delineated an 2 Mb–wide region at 3q26.2 encompassing PDCD10 to MYNN (chr3:168722613-170908630). Ecotropic viral integration site-1 (EVI1) and myelodysplastic syndrome 1 (MDS1) are located at the center of this region, and their DNA copy number increases are associated with at least 5-fold increased RNA transcript levels in 83% and 98% of advanced ovarian cancers, respectively. Moreover, MDS1/EVI1 and EVI1 protein levels are increased in ovarian cancers and cancer cell lines. EVI1 and MDS1/EVI1 gene products increased cell proliferation, migration, and decreased transforming growth factor-ß–mediated plasminogen activator inhibitor-1 promoter activity in ovarian epithelial cells. Intriguingly, the increases in EVI1 DNA copy number and MDS1/EVI1 transcripts are associated with improved patient outcomes, whereas EVI1 transcript levels are associated with a poor patient survival. Thus, the favorable patient prognosis associated with increased DNA copy number seems to be as a result of high-level expression of the fusion transcript MDS1/EVI1. Collectively, these studies suggest that MDS1/EVI1 and EVI1, previously implicated in acute myelogenous leukemia, contribute to the pathophysiology of epithelial ovarian cancer. [Cancer Res 2007;67(7):3074–84]

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