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WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome.

Nunez MI, Rosen DG, Ludes-Meyers JH, Abba MC, Kil H, Page R, Klein-Szanto AJ, Godwin AK, Liu J, Mills GB, Aldaz CM - BMC Cancer (2005)

Bottom Line: Immunoblotting analysis from normal ovarian samples demonstrated consistently strong WWOX expression while 37% ovarian carcinomas showed reduced or undetectable WWOX protein expression levels.The two histotypes showing significant loss of WWOX expression were of the Mucinous (70%) and Clear Cell (42%) types.It was also observed that subsets of ovarian tumors demonstrated loss of WWOX expression and is potentially associated with patient outcome.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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>

ABSTRACT

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).

Conclusion: 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.

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WWOX inmunohistochemical staining in ovarian carcinoma samples by histotypes. A-C. Serous ovarian carcinomas. A, Strong-Moderate. Note heterogeneity in staining intensity pattern in this tumor sample; B, Moderate. Note predominance of apical staining in this papillary serous ovarian carcinoma; C Weak-Negative, WWOX lack of staining observed in approximately 30% of serous carcinoma cases. D-F. Endometroid ovarian carcinomas. D and E positive WWOX cytoplasmic staining and F negative staining. G-I. Clear Cell ovarian Carcinomas. G, representative photomicrograph of one of a moderately WWOX positive CCC case, while H and I, represent typical negative cases. J-L. Mucinous ovarian carcinomas, J, representative mildly positive case and K representative mucinous carcinoma of the endocervicoid subtype with demonstrating no WWOX staining. L, mucinous carcinoma of the intestinal subtype also negative for WWOX staining.
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Figure 3: WWOX inmunohistochemical staining in ovarian carcinoma samples by histotypes. A-C. Serous ovarian carcinomas. A, Strong-Moderate. Note heterogeneity in staining intensity pattern in this tumor sample; B, Moderate. Note predominance of apical staining in this papillary serous ovarian carcinoma; C Weak-Negative, WWOX lack of staining observed in approximately 30% of serous carcinoma cases. D-F. Endometroid ovarian carcinomas. D and E positive WWOX cytoplasmic staining and F negative staining. G-I. Clear Cell ovarian Carcinomas. G, representative photomicrograph of one of a moderately WWOX positive CCC case, while H and I, represent typical negative cases. J-L. Mucinous ovarian carcinomas, J, representative mildly positive case and K representative mucinous carcinoma of the endocervicoid subtype with demonstrating no WWOX staining. L, mucinous carcinoma of the intestinal subtype also negative for WWOX staining.

Mentions: Thirty percent of ovarian carcinomas (133/444) showed loss of WWOX protein expression while 70% (311/444) demonstrated positive staining including cases with very strong staining (Figure 3A–I) (Table 1). Among serous carcinomas, 29% of the cases (109/375) fell in the negative/low group and 71% (266/375) stained moderately or strongly positive. The most typical WWOX staining pattern observed for all histotypes was cytoplasmic and diffuse, no tissues demonstrated any nuclear staining. Interestingly, some of the carcinomas showed a distinctive strong cell membrane staining pattern (Figure 3). Other tumors displayed a predominantly apical border staining, in conjunction with staining of what appeared to be luminal secretions (Figure 3B). Among endometroid carcinomas 23% of the cases (9/40) were negative/low and 77% (31/40) stained moderately or strongly positive for WWOX expression. This histological subtype showed a diffuse and apical cytoplasmic pattern of protein expression (Figure 3D, E). Among the CCC group, 42% of the cases (8/19) were negative/weak while 58% (11/19) stained moderately or strongly for WWOX (Figure 3G–I).


WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome.

Nunez MI, Rosen DG, Ludes-Meyers JH, Abba MC, Kil H, Page R, Klein-Szanto AJ, Godwin AK, Liu J, Mills GB, Aldaz CM - BMC Cancer (2005)

WWOX inmunohistochemical staining in ovarian carcinoma samples by histotypes. A-C. Serous ovarian carcinomas. A, Strong-Moderate. Note heterogeneity in staining intensity pattern in this tumor sample; B, Moderate. Note predominance of apical staining in this papillary serous ovarian carcinoma; C Weak-Negative, WWOX lack of staining observed in approximately 30% of serous carcinoma cases. D-F. Endometroid ovarian carcinomas. D and E positive WWOX cytoplasmic staining and F negative staining. G-I. Clear Cell ovarian Carcinomas. G, representative photomicrograph of one of a moderately WWOX positive CCC case, while H and I, represent typical negative cases. J-L. Mucinous ovarian carcinomas, J, representative mildly positive case and K representative mucinous carcinoma of the endocervicoid subtype with demonstrating no WWOX staining. L, mucinous carcinoma of the intestinal subtype also negative for WWOX staining.
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getmorefigures.php?uid=PMC1173095&req=5

Figure 3: WWOX inmunohistochemical staining in ovarian carcinoma samples by histotypes. A-C. Serous ovarian carcinomas. A, Strong-Moderate. Note heterogeneity in staining intensity pattern in this tumor sample; B, Moderate. Note predominance of apical staining in this papillary serous ovarian carcinoma; C Weak-Negative, WWOX lack of staining observed in approximately 30% of serous carcinoma cases. D-F. Endometroid ovarian carcinomas. D and E positive WWOX cytoplasmic staining and F negative staining. G-I. Clear Cell ovarian Carcinomas. G, representative photomicrograph of one of a moderately WWOX positive CCC case, while H and I, represent typical negative cases. J-L. Mucinous ovarian carcinomas, J, representative mildly positive case and K representative mucinous carcinoma of the endocervicoid subtype with demonstrating no WWOX staining. L, mucinous carcinoma of the intestinal subtype also negative for WWOX staining.
Mentions: Thirty percent of ovarian carcinomas (133/444) showed loss of WWOX protein expression while 70% (311/444) demonstrated positive staining including cases with very strong staining (Figure 3A–I) (Table 1). Among serous carcinomas, 29% of the cases (109/375) fell in the negative/low group and 71% (266/375) stained moderately or strongly positive. The most typical WWOX staining pattern observed for all histotypes was cytoplasmic and diffuse, no tissues demonstrated any nuclear staining. Interestingly, some of the carcinomas showed a distinctive strong cell membrane staining pattern (Figure 3). Other tumors displayed a predominantly apical border staining, in conjunction with staining of what appeared to be luminal secretions (Figure 3B). Among endometroid carcinomas 23% of the cases (9/40) were negative/low and 77% (31/40) stained moderately or strongly positive for WWOX expression. This histological subtype showed a diffuse and apical cytoplasmic pattern of protein expression (Figure 3D, E). Among the CCC group, 42% of the cases (8/19) were negative/weak while 58% (11/19) stained moderately or strongly for WWOX (Figure 3G–I).

Bottom Line: Immunoblotting analysis from normal ovarian samples demonstrated consistently strong WWOX expression while 37% ovarian carcinomas showed reduced or undetectable WWOX protein expression levels.The two histotypes showing significant loss of WWOX expression were of the Mucinous (70%) and Clear Cell (42%) types.It was also observed that subsets of ovarian tumors demonstrated loss of WWOX expression and is potentially associated with patient outcome.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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>

ABSTRACT

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).

Conclusion: 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.

Show MeSH
Related in: MedlinePlus