Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary.
OBJECTIVE
Low-grade serous carcinoma (LGSC) is a chemoresistant ovarian neoplasm thought to potentially arise in a background of low malignant potential tumors (LMP), which are typically non-aggressive. However, LMP with micropapillary features (LMP-MP) have more aggressive clinical behavior and may represent an intermediate in progression to LGSC. The objective of this study was to obtain and compare gene expression profiles of LMP, LMP-MP and LGSC to determine if LMP-MP more closely resembles LGSC, and to identify genes involved in LGSC carcinogenesis.


METHODS
Epithelial cells from LMP (n=17), LMP-MP (n=9) and LGSC (n=11) were isolated by laser capture microdissection. RNA was extracted, reverse transcribed to cDNA, amplified and hybridized to Affymetrix U133 Plus2 genechip arrays. Gene expression data were checked for quality, filtered and significantly altered genes between subgroups were identified. Differential expression of selected genes was verified by RT-qPCR and immunohistochemistry.


RESULTS
Gene expression analysis identified differential expression between LMP and LMP-MP, LMP and LGSC but not LMP-MP and LGSC. Integration of differentially expressed genes into the protein interaction database CytoScape highlighted gene products in the MAPK pathway as differentially regulated between LMP and LGSC. Four genes were selected and validated by RT-qPCR performed on microarray samples (n=15) and immunohistochemistry on a representative microarray (n=57).


CONCLUSIONS
The gene expression profile of LMP-MP is similar to LGSC and distinct from LMP, reflecting their more aggressive clinical behavior. Candidate genes in the MAPK pathway were highlighted which may play a role in LGSC carcinogenesis and indicate potential therapeutic targets.
May
Taymaa
T
Department of Obstetrics and Gynecology, University of Toronto, Canada.
Virtanen
Carl
C
Sharma
Monika
M
Milea
Anca
A
Begley
Heather
H
Rosen
Barry
B
Murphy
K Joan
KJ
Brown
Theodore J
TJ
Shaw
Patricia A
PA
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; C484406:TANK protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2