Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer.

Abstract

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 p110alpha catalytic subunit of phosphoinositide-3-kinase (PI3KCA) and protein kinase Ciota (PKCiota) 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 approximately 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-beta-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.

• Authors: Meera Nanjundan, Yasuhisa Nakayama, Kwai Wa Cheng, John Lahad, Jinsong Liu, Karen Lu, Wen-Lin Kuo, Karen Smith-McCune, David Fishman, Joe W Gray, Gordon B Mills
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 7 Pg. 3074-84 (Apr 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17409414 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA, Neoplasm
• DNA-Binding Proteins
• MDS1 and EVI1 Complex Locus Protein
• MECOM protein, human
• RNA, Messenger
• Transcription Factors

Topics

• Cell Line, Tumor
• Chromosomes, Human, Pair 3 (genetics)
• DNA, Neoplasm (genetics)
• DNA-Binding Proteins (biosynthesis, genetics)
• Epithelial Cells (metabolism)
• Female
• Gene Amplification
• Gene Dosage
• Humans
• MDS1 and EVI1 Complex Locus Protein
• Neoplasm Staging
• Nucleic Acid Hybridization
• Ovarian Neoplasms (genetics, metabolism, pathology)
• Prognosis
• Protein Structure, Tertiary
• Proto-Oncogenes (genetics)
• RNA, Messenger (biosynthesis, genetics)
• Transcription Factors (biosynthesis, genetics)