Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer.
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.
Nanjundan
Meera
M
Department of Molecular Therapeutics, M. D. Anderson Cancer Center, University of Texas, Houston, Texas, USA. mnanjund@mdanderson.org
Nakayama
Yasuhisa
Y
Cheng
Kwai Wa
KW
Lahad
John
J
Liu
Jinsong
J
Lu
Karen
K
Kuo
Wen-Lin
WL
Smith-McCune
Karen
K
Fishman
David
D
Gray
Joe W
JW
Mills
Gordon B
GB
D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D009367:Neoplasm Staging; D009693:Nucleic Acid Hybridization; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D017434:Protein Structure, Tertiary; D011519:Proto-Oncogenes / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D012333:RNA, Messenger; D014157:Transcription Factors