WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome.
BACKGROUND
The putative tumor suppressor WWOX gene spans the common chromosomal fragile site 16D (FRA16D) at chromosome area 16q23.3-24.1. This region is a frequent target for loss of heterozygosity and chromosomal rearrangement in ovarian, breast, hepatocellular, prostate carcinomas and other neoplasias. The goal of these studies was to evaluate WWOX protein expression levels in ovarian carcinomas to determine if they correlated with clinico-pathological parameters, thus providing additional support for WWOX functioning as a tumor suppressor.


METHODS
We performed WWOX protein expression analyses by means of immunobloting and immunohistochemistry on normal ovaries and specific human ovarian carcinoma Tissue Microarrays (n = 444). Univariate analysis of clinical-pathological parameters based on WWOX staining was determined by chi2 test with Yates' correction. The basic significance level was fixed at p < 0.05.


RESULTS
Immunoblotting analysis from normal ovarian samples demonstrated consistently strong WWOX expression while 37% ovarian carcinomas showed reduced or undetectable WWOX protein expression levels. The immunohistochemistry of normal human ovarian tissue sections confirmed strong WWOX expression in ovarian surface epithelial cells and in epithelial inclusion cysts within the cortex. Out of 444 ovarian carcinoma samples analyzed 30% of tumors showed lack of or barely detectable WWOX expression. The remaining ovarian carcinomas (70%) stained moderately to strongly positive for this protein. The two histotypes showing significant loss of WWOX expression were of the Mucinous (70%) and Clear Cell (42%) types. Reduced WWOX expression demonstrated a significant association with clinical Stage IV (FIGO) (p = 0.007), negative Progesterone Receptor (PR) status (p = 0.008) and shorter overall survival (p = 0.03).


CONCLUSIONS
These data indicate that WWOX protein expression is highly variable among ovarian carcinoma histotypes. It was also observed that subsets of ovarian tumors demonstrated loss of WWOX expression and is potentially associated with patient outcome.
Nunez
María I
MI
Department of Carcinogenesis, The University of Texas M,D, Anderson Cancer Center, Science Park-Research Division, Smithville TX, USA. minunez@mdanderson.org <minunez@mdanderson.org>
Rosen
Daniel G
DG
Ludes-Meyers
John H
JH
Abba
Martín C
MC
Kil
Hyunsuk
H
Page
Robert
R
Klein-Szanto
Andres J P
AJ
Godwin
Andrew K
AK
Liu
Jinsong
J
Mills
Gordon B
GB
Aldaz
C Marcelo
CM
D015153:Blotting, Western; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism*; D010088:Oxidoreductases / Q000096:biosynthesis*; D011980:Receptors, Progesterone / Q000096:biosynthesis; D013997:Time Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase
D011980:Receptors, Progesterone; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human