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. 2008 Sep;10(9):1021–1027. doi: 10.1593/neo.08474

Expression of Class I Histone Deacetylases Indicates Poor Prognosis in Endometrioid Subtypes of Ovarian and Endometrial Carcinomas1

Wilko Weichert *, Carsten Denkert *, Aurelia Noske *, Silvia Darb-Esfahani *, Manfred Dietel *, Steve E Kalloger †, David G Huntsman †, Martin Köbel †
PMCID: PMC2517648  PMID: 18714364

Abstract

Histone deacetylase (HDAC) inhibitors are an emerging class of targeted cancer therapeutics, and little is known about HDAC expression in gynecologic malignancies. Therefore, we tested the hypothesis whether high-level expression of class 1 HDACs (HDAC1, 2, and 3) is associated with clinically distinct subsets of ovarian and endometrial carcinomas. Expression was assessed by immunohistochemistry in a population-based cohort of 465 ovarian and 149 endometrial carcinomas and correlated with clinicopathologic parameters. Each of the HDACs was expressed at high levels in most ovarian (HDAC1, 61%; HDAC2, 93%; HDAC3, 84%) and endometrial (HDAC1, 61%; HDAC2, 95%; HDAC3, 83%) carcinomas. Further, 55% and 56% of ovarian and endometrial carcinomas, respectively, expressed all three HDACs at high levels. Such cases were less common among endometrioid subtypes of ovarian and endometrial carcinomas (36% and 52% positive cases, respectively) compared with high-grade serous subtypes (64 and 69%, respectively, P < .001). High-level expression of all three HDACs is associated with a poor prognosis in ovarian endometrioid carcinomas (hazard ratio, 6.7; 95% confidence interval, 1.9–23.3). The independent prognostic information and the overall high rate of expression for class I HDACs suggest that these targets should be explored as predictive factors in ovarian and endometrial carcinomas prospectively.

Introduction

Current treatment strategies for ovarian carcinomas with high-risk histology (e.g., high-grade serous and clear cell subtype) are still ineffective [1]. Even in stage I/II, 30% to 40% of women with these neoplasms will die of their disease [2]. For endometrial carcinomas of the serous and clear cell type, the prognosis is comparably grim [3]. Consequently, novel target-based chemotherapeutic strategies are urgently needed. Conversely, endometrioid carcinomas of the ovary and endometrium, which sometimes present synchronously [4], are less-aggressive tumors compared with their high-risk counterparts. The great majority of women (approximately 80%) will be cured by surgery alone because these tumors are frequently organ confined and tend to metastasize late [5–7]. Because there is no good strategy to predict the natural course of these tumors, more than 90% of ovarian endometrioid carcinomas are still treated with platinum-based chemotherapy, and a large percentage of endometrial endometrioid carcinomas are treated with adjuvant radiotherapy and chemotherapy [8,9]. Along with the opportunity of subtype-specific targeted therapy, there is a need to test for novel markers that will help to classify patient risk independent of currently known risk factors.

Histone modifications are known to be centrally involved in the malignant transformation of cells and histone deacetylase (HDAC) inhibitors have proven to be effective as anticancer agents in a broad variety of tumors [10–13]. The family of HDACs to date comprises 18 isoenzymes, which, on the basis of structure, could be subclassified into four classes [11], with class I HDACs being the most thoroughly investigated with respect to function and relevance for tumor formation and progression. Lately, research on these proteins has gained momentum because small-molecule inhibitors of HDACs are now available and are currently tested as new antitumor drugs in late-phase clinical studies for different types of solid tumors [12,13], including ovarian cancer [14]. In addition, the HDAC inhibitor vorinostat has recently been approved for therapy in cutaneous T-cell lymphoma [15].

Histone deacetylase inhibitors are known to have profound antitumor effects in both endometrial [16–20] and ovarian carcinoma cell lines [17,21–23] most likely by inducing cell cycle arrest, apoptosis, and differentiation. These drugs act synergistically with paclitaxel- [24,25] and platinum-based chemotherapeutics [26,27] in vitro.

We have previously found class I HDACs to be highly expressed in different types of human cancers [28–30]. In addition, class I HDAC expression was an unfavorable independent prognostic factor in some of these tumor entities. Currently, little is known about HDAC expression in gynecologic malignancies [23,31].

In our study, we focused on this apparent lack of translational research in this field and addressed the question whether class I HDACs are expressed in gynecologic malignancies and whether expression patterns vary with respect to clinicopathologic and prognostic patient subgroups.

Materials and Methods

Study Population

From a population-based cohort of 3501 patients with ovarian carcinoma in British Columbia diagnosed between 1984 and 2000, 518 cases were selected on the basis of optimal surgical treatment (i.e., no macroscopic residual tumor after primary surgery) and were eligible for tissue microarray (TMA) construction after complete gynecopathologic review [5]. Two hundred consecutive cases of endometrial carcinoma were retrieved from the archives of the Department of Pathology, Vancouver General Hospital, for the period 1983–1998. All cases underwent gynecopathologic review. Mixed carcinomas were classified according to their highest-grade component and included if the high-grade component was sampled on the TMA. Clinical and pathologic data are shown in Table 1. Both series of cases have been the subject of previous studies [32,33]. A representative area of each tumor was selected and duplicate 0.6-mm tissue cores were punched to construct a TMA (Beecher Instruments, Silver Springs, MD).

Table 1.

Distribution of Ovarian and Endometrial Carcinomas across Stage.

Cell Type N (%) Stage I/II (%) Stage III (%) Age (Mean ± SE)
Ovarian carcinoma (all) 465 83 17 58.0 ± 13
High-grade serous 180 (39%) 66 34 60.9 ± 12
Clear cell 122 (27%) 93 7 56.4 ± 13
Endometrioid 114 (24%) 96 4 55.8 ± 13
Mucinous 24 (5%) 100 0 55.4 ± 13
Other 25 (5%) 88 12 60.9 ± 11
Endometrial carcinoma (all) 149 87 13 63.5 ± 13
Endometrioid 127 (85%) 93 7 63.0 ± 13
Serous 13 (9%) 46 54 70.1 ± 8
Clear cell 6 (4%) 83 17 65.5 ± 17
Other 3 (2%) 67 33 58.7 ± 12
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Adjuvant Therapy and Follow-up

None of the included cases received preoperative radiotherapy or chemotherapy. Approximately 97% of ovarian carcinoma patients were treated according to the provincial treatment guidelines of the British Columbia Cancer Agency [8]. On the other hand, 3% of patients refused the advised chemotherapy and were excluded from survival analysis. All patients with endometrial carcinomas were treated according the BC Cancer Agency treatment recommendation. All women underwent initial simple hysterectomy and bilateral salpingo-oophorectomy. For those with documented widespread disease, debulking surgery as in ovarian carcinomas was performed. Subsequently, radiation was added if the likelihood of local recurrence was >10%, and chemotherapy with different regimens was given if the predicted risk of death was >25%. Systematic lymph node dissection was not routinely performed. Outcomes were tracked through the Cheryl Brown Ovarian Cancer Outcomes Unit at the British Columbia Cancer Agency and were available for all patients. Median follow-up time was 5.1 and 6.2 years for ovarian and endometrial carcinomas, respectively. Approval for the study was obtained from the Research Ethics Board of the University of British Columbia.

Immunohistochemistry

Serial 4-µm sections were cut for immunohistochemical analysis and run through an automated system by Ventana, Tuscon, AZ, as per manufacturer's protocol. Polyclonal rabbit anti-HDAC1 antibody and monoclonal mouse anti-HDAC2 antibody were obtained from Abcam, Cambridge, UK. Monoclonal mouse anti-HDAC3 antibody was obtained from Becton Dickinson, Franklin Lakes, CA. Ample confirmation of antibody specificity has been performed in previous studies [28–30].

Evaluation of Immunohistochemistry

Tissue microarrays were scored for HDAC1, HDAC2, and HDAC3 by a pathologist (M.K.; scans available online: http://bliss.gpec.ubc.ca/ under OOU ovarian carcinomas, under 02-005 endometrial carcinomas). Only nuclear staining within tumor cells was considered for evaluation. A four-tiered scoring system was used: 0 for negative cases, +1 for weak intensity, +2 for moderate intensity, and +3 for strong intensity (Figure 1). To optimize for disease-specific survival differences, the raw data were binarized as follows: the moderate (+2) and strong (+3) cases were grouped for statistical analysis and assigned the designation 1 and considered as high-level expressors, whereas the completely negative (0) and weak (+1) cases were considered HDAC low-level expressors and designated as 0. In addition, cases were grouped as being high for all three HDACs versus others. In total, 53 (10%) ovarian carcinoma and 51 (26%) endometrial carcinomas were not interpretable at least for one marker, and all analyses were restricted to cases with complete information.

Figure 1.

Figure 1

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HDAC expression: (A to D) HDAC1 expression in endometrial endometrioid carcinomas score 0 (A), score 1 (B), score 2 (C), score 3 (D); (B) insert normal proliferative endometrium. (E) HDAC2 expression in ovarian clear cell carcinoma, score 3. (F) HDAC3 expression in ovarian high-grade serous carcinoma, score 3.

Statistical Analysis

Univariable survival analysis was performed by the generation of Kaplan-Meier curves, and differences between the groups were assessed using the log rank statistic. Multivariable survival analysis was performed using the Cox proportional hazards model. Contingency tables and the Pearson χ2 statistic were used to test the change in the distribution of HDAC expression across primary cell types. The Kruskal-Wallis test was used to compare medians for continuous variables (Ki-67). Spearman rank order correlation was used to determine whether there was a positive or negative correlation between the levels of expression shown by any two types of immunostaining. All analyses were performed using SPSS v15.0 (SPSS Inc, Chicago, IL). P values < .05 were considered significant.

Results

Expression Patterns of Class I HDAC Isoforms in Normal Tissue

HDAC1, HDAC2, and HDAC3 are expressed weakly in nuclei of ovarian surface epithelium of normal ovaries (n = 5). Expression of all class I isoforms in normal endometrium and in ovarian endometriosis was variable but did not exceed moderate staining intensity. Normal endometrial stroma cells and inflammatory cells, if present, partly showed moderate staining intensity as well.

Expression Patterns of Class I HDAC Isoforms in Ovarian Carcinomas

Most ovarian carcinomas expressed high levels of HDAC1 (61%), HDAC2 (93%), and HDAC3 (84%) in the nuclei of tumor cells (Figure 1 and Table 2). Cytoplasmic tumor cell expression was not observed. Stromal cells and inflammatory cells were occasionally positive. Generally, HDAC2 had the highest expression level in all tumor subtypes. Expression of class I HDAC isoforms correlated with each other: HDAC1 with HDAC2 (r = 0.150, P = .001), HDAC1 with HDAC3 (r = 0.300, P < .001), and HDAC2 with HDAC3 (r = 0.265, P = .001), suggesting a shared functional regulation. High-level expression of all three isoforms was detected in 55% of ovarian carcinomas with the mucinous subtype of ovarian carcinoma showing the highest frequency (71%), followed by high-grade serous (64%), clear cell (54%), and endometrioid subtypes (36%). These expression levels are indicative of significant differential expression (P < .001).

Table 2.

HDAC Expression across Ovarian and Endometrial Carcinoma Subtypes.

Cell Type N HDAC1-Positive Cases (%) HDAC2-Positive Cases (%) HDAC3-Positive Cases (%) All Three HDACs-Positive Cases (%)
Ovarian carcinoma 465 61 93 84 55
High-grade serous 180 67 98 92 64
Clear cell 122 64 86 77 54
Endometrioid 114 45 94 78 36
Mucinous 24 83 75 83 71
Other 25 64 100 92 64
Endometrial carcinoma 149 61 95 83 56
Endometrioid 127 58 94 81 52
Serous 13 69 100 100 69
Clear cell 6 83 100 83 83
Other 3 100 100 100 100
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Other ovarian carcinomas include nine low-grade serous, six transitional, six undifferentiated, and four adenocarcinoma not otherwise specified.

Other endometrial carcinomas include two small cell carcinomas and one large cell carcinoma.

Expression Patterns of Class I HDAC Isoforms in Endometrial Carcinomas

In parallel to the results reported for ovarian carcinomas, most endometrial carcinomas expressed class I HDAC isoforms in the nuclei of tumor cells (HDAC1, 61%; HDAC2, 95%; HDAC3, 83%; Table 2 and Figure 1). As for ovarian carcinomas, clear cell (83%) and serous subtypes (69%) showed significantly higher expression rates for all three HDACs than endometrioid carcinomas (52%, P < .001; Table 2). In all tumor types, the expression of HDAC2 was highest, followed by HDAC3 and HDAC1 (Table 2). Expression of HDAC isoforms showed a moderate degree of correlation with one another: HDAC1 with HDAC2 (r = 0.321, P < .001), HDAC1 with HDAC3 (r = 0.512, P < .001), and HDAC2 with HDAC3 (r = 0.339, P < .001). Neither in ovarian nor in endometrial carcinomas a significant association of HDAC1, HDAC2, or HDAC3 expression with stage within histologic subtypes was observed (data not shown).

Correlation of Class I HDAC Expression with Proliferation

Because data from cell culture studies suggest a tight interlink between HDACs and cell proliferation [34,35], we aimed to test this potential association for ovarian and endometrial carcinomas in vivo. Those tumors showing higher proliferative capacity as determined by Ki-67 staining usually expressed higher levels of all three class I HDAC isoforms, in both ovarian (P < .001) and endometrial carcinomas (P < .001). This significant association was also observed in most of the major subtypes, with the exception of ovarian endometrioid carcinomas, which showed a borderline significance of (P = .05; Figure 2).

Figure 2.

Figure 2

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Box-percentile plot of Ki-67 labeling index in ovarian carcinoma subtypes. HG serous (indicates high-grade serous), clear cell, and endometrioid ovarian carcinoma and endometrioid subtype of endometrial carcinomas subdivided by low (blue) versus high (red) expression of all three HDACs. P values, Kruskal-Wallis test.

Correlation of Class I HDAC Expression with Patient Prognosis

High-level expression of all three class I HDACs was significantly associated with decreased disease-specific survival in endometrioid ovarian cancer (Figure 3A; P = .007). In this tumor type, 10-year disease-specific survival of women with tumors expressing all three isoforms at high levels was 67% compared with those patients whose tumors expressed no or only some isoforms with 93%. This effect was mainly due to a significant association of HDAC1 expression with prognosis (HDAC1, P = .012; HDAC2, P = .598; HDAC3, P = .391). In multivariable survival analysis performed under inclusion of age, FigO stage, Silverberg grade, and all three class I HDACs, HDAC expression retained its independent statistical significance (hazard ratio [HR], 6.7, P = .003; Table 3). In serous (Figure 3B; P = .756), mucinous, and clear cell carcinomas (data not shown) of the ovary, none of the HDAC isoforms had significant impact on patient prognosis in univariate survival analysis.

Figure 3.

Figure 3

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Kaplan-Meier survival analysis: (A) ovarian endometrioid carcinomas (N = 114); (B) ovarian high-grade serous carcinomas (N = 180); (C) endometrial endometrioid carcinomas (N = 127). P values, log rank test.

Table 3.

Univariable and Multivariable Analyses of Disease-Specific Survival for Ovarian Endometrioid Carcinomas (N = 114/15 Events).

Patient Characteristics Risk Factor Univariable Analysis Multivariable Analysis
HR 95% CI P HR 95% CI P
Age * 0.423 * 0.246
Stage I/II 1.0 0.001 1.0 0.0002
III 9.3 2.5–34.0 16.9 3.8–75.4
Silverberg grade 1 1.0 0.264 1.0 0.408
2 1.7 0.5–5.2 1.3 0.4–1.3
3 3.5 0.7–16.7 3.1 0.6–15.7
All three HDACs 0 1.0 0.007 1.0 0.003
1 4.9 1.5–15.7 6.7 1.9–23.3
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CI indicates confidence interval; HR, hazard ratio.

*

Hazard ratio for age is not available because it is a continuous variable.

In endometrial endometrioid carcinomas, 10-year disease-specific survival of women with tumors expressing all three isoforms at high levels was 63% compared with those patients whose tumors expressed no or only some isoforms with 83%. Although this was not statistically significant (Figure 3C; P = .123), the survival difference was similar to that observed in their ovarian counterparts (20% vs 26%). In multivariable analysis under inclusion of age, FigO stage, grade, and grouped HDAC expression, class I HDAC expression showed a trend toward unfavorable prognosis (HR, 2.0, P = .151; Table 4).

Table 4.

Univariable and Multivariable Analyses of Disease-Specific Survival for Endometrial Endometrioid Carcinomas (N = 123/20 Events).

Patient Characteristics Risk Factor Univariable Analysis Multivariable Analysis
HR 95% CI P HR 95% CI P
Age * 0.0004 * 0.001
Stage I 1.0 0.005 1.0 0.133
II/III 3.6 1.4–8.9 2.1 0.8–5.8
WHO Grade 1 1.0 0.042 1.0 0.052
2 1.0 0.2–4.4 0.5 0.1–2.6
3 3.1 1.2–7.9 2.5 0.9–6.8
All three HDACs 0 1.0 0.123 1.0 0.151
1 2.1 0.8–5.4 2.0 0.8–5.4
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*

Hazard ratio for age is not available because it is a continuous variable.

Discussion

In this study, we describe a high-level expression of class I HDAC isoforms in ovarian and endometrial carcinomas. Histone deacetylase expression is especially prominent in high-grade tumors of serous and clear cell subtype. In the endometrioid subtype, we show that expression of the three class I HDACs is an independent prognostic marker. Reports on in vivo expression of single HDAC isoforms in ovarian and endometrioid carcinomas are sparse. In a small set of 10 ovarian carcinomas, high expression levels for class I HDACs were reported [23], which is in line with our results. However, in this cohort, it was not possible to test for prognosis or clinical correlations.

Although, in our study, a significant unfavorable prognostic association of class I HDACs for endometrioid tumor subtypes was only observed for ovarian but not for endometrial carcinomas, the same trend and similar differences in 10-year survival rates for class I HDAC expressing groups were evident for tumors arising in both organs. The reason for the differences between ovarian and endometrial carcinomas might be a different assembly of the patient cohorts. The ovarian carcinoma patients were recruited from a population-based cohort from British Columbia and restricted to patients with completely resectable disease after primary surgery. Patients with endometrial carcinoma were selected from a cohort treated at the Vancouver General Hospital, which is a specialized center where patients with high-risk disease are referred for surgery. This is reflected by a higher number of grade 3 carcinomas in the endometrial endometrioid group (24%) compared to other hospital-based cohorts of endometrioid endometrial carcinoma (6%) [6] and to the ovarian endometrioid group (7%, P = .002, Pearson χ2). In multivariable analysis, grade and age had a stronger influence on prognosis of endometrial endometrioid than ovarian endometrioid carcinomas. Nevertheless, based on presumably similar biology and given the fact that both tumors occur synchronously in a significant proportion of patients [4], we think that the findings in ovarian endometrioid carcinomas could be transferable to their endometrial counterpart. Larger numbers might be needed to confirm these finding in endometrial endometrioid carcinomas.

Previous immunohistochemical studies of HDAC isoform expression have been published for gastric [28], colorectal [29], prostate [30], and breast [34] cancers by our group and others. In colorectal cancers, class I HDAC expression was associated with poor prognosis [29]. Because colorectal carcinomas show pathogenetic pathways (e.g., microsatellite instability, β-catenin mutation, K-Ras mutation) strikingly similar to endometrioid carcinomas [35,36], similar prognostic effects of HDAC expression might be not surprising.

In the entire cohort and in each subtype, class I HDAC expression is pronounced in highly proliferating tumors as determined by high Ki-67 labeling index. These data fit well with results from functional in vitro studies showing that HDAC inhibitors induce cell cycle arrest in ovarian and endometrial cancer cell lines [17–23].

Our observation that HDAC expression levels vary considerably and have impact on patient survival in ovarian endometrioid carcinoma implicates that expression of these proteins might be useful as a prognostic marker. The absence of or only partial expression of class I HDACs indicates a very good prognosis (a 93% 10-year disease-specific survival). Because 94% of these patients received adjuvant platinum-based chemotherapy, we are not able to compare the outcome with a nontreated group. Anecdotally from seven patients, where adjuvant chemotherapy was not advised, only one woman died of disease, and this tumor expressed a high level of all three HDACs. Further, if we estimate the cure rate of women in the chemotherapy group by using the effectiveness of chemotherapy (33% of patients are cured by adjuvant therapy) described by the authors of the Action trial [37], we calculate that 7% died despite chemotherapy and only 4% of our patients were actually cured by chemotherapy; hence, 89% were treated without benefit. Therefore, we would hypothesize that HDACs' expression assessment can identify candidates that can be spared from first-line chemotherapy to minimize overtreatment. Future larger studies might clarify whether it is necessary to assess an antibody panel against all three HDACs or whether this prognostic effect is largely based on the expression of one isoform, e.g., HDAC1.

An even more interesting aspect of our results is that response of HDAC inhibitors might vary with different expression levels of class I HDACs. Treatment of tumors expressing low levels of HDACs might be ineffective because it has been shown that HDAC-negative tumors caused by the mutation of HDAC genes are resistant to HDAC inhibitors [38]. Hence, we hypothesize that class I HDAC expression in ovarian and endometrial carcinomas might be associated with a positive response to HDAC inhibitors. This would be especially desirable in endometrioid subtypes, because those patients that highly express class I HDACs have a compromised prognosis. Because determination of class I HDAC expression status in tumor tissue is easy, straightforward, and possible on very small tissue samples such as the 0.6-mm cores on a tissue microarray, such analysis is feasible in clinical trials. As we have shown subtype-specific differences in the prognostic value, it is possible that predictive effects will also be restricted to specific pathologic subtypes.

Abbreviations

HDAC

histone deacetylase

TMA

tissue microarray

HG serous

high-grade serous

Footnotes

1

This work was supported by the Cheryl Brown Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency and by an unrestricted educational grant from sanofiaventis. M.K. received fellowship support from Eli Lilly Canada.

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