[Show abstract][Hide abstract] ABSTRACT: Background The use of flaps in vulvar cancer-related reconstruction has been increasing, but few studies have evaluated the outcome and quality of life of patients after this surgery. The purpose of this study was to evaluate the outcomes of vulvar reconstruction using musculocutaneous/skin flaps in patients with advanced and recurrent vulvar malignancies. Methods Patients with vulvar malignancies who underwent vulvar reconstruction using different types of flaps were retrospectively reviewed. Patient outcomes were evaluated with a focus on quality of life and prognosis. Results Thirty-six patients were enrolled, 58.33 % of them used anterolateral thigh flap (ALT), 16.67 % of them used pudendal thigh flap (PTF), 11.11 % of them used deep omferior epigastric perforator (DIEP) and gracilis myocutaneous flap were used in 2.78 % of the patients, the other 11.11 % patients used two types of flaps. Eleven patients (30.56 %) developed complications, including 5 patients (13.89 %) with partial necrosis, 5 (13.89 %) with minimal wound dehiscence and 1 (2.78 %) with flap cellulitis. All patients who developed partial necrosis (13.89 %) underwent reoperation. The mean verbal rating scale score was 1.44 before reconstruction and 0.17 after surgery (P < 0.0001). The mean performance status was 1.67 before surgery and improved to 0.31 after surgery (P < 0.0001). The median overall follow-up time after vulvar reconstruction was 9 months. Twenty-one patients (58.3 %) developed recurrence at a median interval of 5 months after vulvar reconstruction. After a median follow-up time of 14 months, 41.7 % of the patients were living and disease-free. The 5-year survival of the 36 patients was 53.8 %. Conclusion Soft tissue reconstruction in patients undergoing resection of advanced/recurrent vulvar malignances is associated with a low rate of postoperative complications, decreased pain, and improved functional status. Although the recurrence rate in this patient population is high, a reasonable proportion of patients who undergo resection for advanced/recurrent vulvar cancer and reconstructive surgery appear to benefit.
BMC Cancer 12/2015; 15(1). DOI:10.1186/s12885-015-1792-x · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Thin endometrium is associated with poor reproductive outcomes; estrogen treatment can increase endometrial thickness (EMT). The aim of this retrospective cohort study was to investigate the factors influencing the effectiveness of estrogen treatment and reproductive outcomes after the treatment in patients with thin endometrium.
Relevant clinical data of 101 patients with thin endometrium who had undergone estrogen treatment were collected. Possible factors influencing the effectiveness of treatment were analyzed retrospectively by logistic regression analysis. Eighty-seven infertile women without thin endometrium who had undergone assisted reproduction served as controls. The cases and controls were matched for age, assisted reproduction method, and number of embryos transferred. Reproductive outcomes of study and control groups were compared using Student's t-test and the Chi-square test.
At the end of estrogen treatment, EMT was ≥8 mm in 93/101 patients (92.1%). Effectiveness of treatment was significantly associated with maximal pretreatment EMT (P = 0.017) and treatment duration (P = 0.004). The outcomes of assisted reproduction were similar in patients whose treatment was successful in increasing EMT to ≥8 mm and the control group. The rate of clinical pregnancy in patients was associated with the number of good-quality embryos transferred in both fresh (P = 0.005) and frozen-thawed (P = 0.000) embryo transfer cycles.
Thinner EMT before estrogen treatment requires longer treatment duration and predicts poorer treatment outcomes. The effectiveness of treatment depends on the duration of estrogen administration. Assisted reproductive outcomes of patients whose treatment is successful (i.e., achieves an EMT ≥8 mm) are similar to those of controls. The quality of embryos transferred is an important predictor of assisted reproductive outcomes in patients treated successfully with exogenous estrogen.
Chinese medical journal 11/2015; 128(23):3173. DOI:10.4103/0366-6999.170258 · 1.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: DNA methylation is clinically relevant to important tumorigenic mechanisms. This study evaluated the methylation status of candidate genes in cervical neoplasia and determined their diagnostic performance in clinical practice. Cervical cancer and normal cervix tissue was used to select the top 5 discriminating loci among 27 loci in 4 genes (CCNA1, CADM1, DAPK1, JAM3), and one locus of JAM3 (region M4) was identified and confirmed with 267 and 224 cervical scrapings from 2 independent colposcopy referral studies. For patients with atypical squamous cells of unknown significance and those with low-grade squamous intraepithelial lesion, with JAM3-M4 compared to a triage marker of hrHPV testing, the specificity for cervical intraepithelial neoplasia 3 CIN3 and cancer cases (CIN3+) / no neoplasia and CIN1 (CIN1-) was significantly increased, from 21.88 to 81.82 and 15.38 to 85.18, respectively. The corresponding positive predictive value (PPV) was increased from 26.47 to 57.14 and 18.52 to 63.64, respectively. For hrHPV-positive patients, compared to a triage marker of cytology testing, JAM3-M4 showed increased specificity and PPV, from 30.67 to 87.65 and 38.82 to 82.14, respectively. We assessed whether JAM3-M4 could distinguish productive from transforming CIN2; the coincidence rate of JAM3-M4 and P16 was as high as 60.5%.
[Show abstract][Hide abstract] ABSTRACT: Cellular exosomes are involved in many disease processes and have the potential to be used for diagnosis and treatment. In this study, we compared the characteristics of exosomes derived from human ovarian epithelial cells (HOSEPiC) and three epithelial ovarian cancer cell lines (OVCAR3, IGROV1, and ES-2) to investigate the differences between exosomes originating from normal and malignant cells. Two established colloid-chemical methodologies, electron microscopy (EM) and dynamic light scattering (DLS), and a relatively new method, nanoparticle tracking analysis (NTA), were used to measure the size and size distribution of exosomes. The concentration and epithelial cellular adhesion molecule (EpCAM) expression of exosomes were measured by NTA. Quantum dots were conjugated with anti-EpCAM to label exosomes, and the labeled exosomes were detected by NTA in fluorescent mode. The normal-cell-derived exosomes were significantly larger than those derived from malignant cells, and exosomes were successfully labeled using anti-EpCAM-conjugated quantum dots. Exosomes from different cell lines may vary in size, and exosomes might be considered as potential diagnosis biomarkers. NTA can be considered a useful, efficient, and objective method for the study of different exosomes and their unique properties in ovarian cancer.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
To compare the clinicopathologic features and prognosis of Chinese patients with ovarian clear cell carcinoma (CCC) and serous carcinoma (SC).
A retrospective cohort study was designed to investigate the clinicopathologic characteristic and prognosis of patients with CCC and SC who were diagnosed and treated in in a tertiary referral center (Peking Union Medical College Hospital) between 1999 and 2009. The Kaplan-Meier method and Cox regression were employed in the survival analysis.
A total of 504 cases were included in the study, comprising 197 cases of CCC and 307 cases of SC. The mean age of the patients with SC was greater than of CCC patients (3.6±0.94, P<0.001). Patients with CCC were more likely to be early-stage and optimally debulked (P<0.001). Regarding cancer-antigen 125, 22% of the patients with CCC had normal values, and the level was significantly lower than in patients with SC (P<0.001). More CCC patients had platinum-resistant tumors compared with platinum-sensitive disease (45.7% in CCC vs. 61.0% in SC [P=0.008]). The 5-year survival rate was 51.2% in the CCC group vs. 49.8% in the SC group (P=0.428). Patients with advanced CCC had a statistically significant poorer overall survival (OS) compared with their SC counterparts (38.0 vs. 52.0 months; hazard ratio 1.584, 95% confidence interval [CI] 1.167-2.150, P=0.003). However, the advantage of improved progression-free survival (PFS) existed across all stages.
Women with ovarian CCC presented at a younger age and early stage. Patients with ovarian CCC also had improved PFS, but they had similar OS compared to patients with SC. However, patients with advanced CCC had decreased survival.
PLoS ONE 07/2015; 10(7-7):e0133498. DOI:10.1371/journal.pone.0133498 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore the genetic and molecular events that control subclones exhibiting distinct invasive/migratory capacities derived from human epithelial ovarian cancer (EOC) cell line A2780 and SKOV3.
Single-cell subclones were isolated and established that were derived from the SKOV3 and A2780 cell lines through limiting dilution methodology. Transwell insert assays and MTT assays were performed to screen and identify the subclones exhibiting the highest and the lowest invasive/migratory capacities, and the selected subclones were renamed as A-H (A2780 high), A-L (A2780 low), S-H (SKOV3 high), and S-L (SKOV3 low). Their biological characteristics were evaluated. RNA-Seq was conducted on the targeted subclones.
Compared with their corresponding counterparts, A-H/S-H cells exhibited significantly higher invasive/migratory capacities (P < 0.001 and = 0.001, respectively). A-H/S-H cells displayed a clear reduction in doubling time (P = 0.004 and 0.001, respectively), and a significant increase in the percentage of cells in S phase (P = 0.004 and 0.022, respectively). Additionally, the apoptotic rates of A-H/S-H cells were significantly lower than those of A-L/S-L cells (P = 0.002 and 0.026, respectively). At both mRNA and protein levels, caspase-3 and caspase-7 expression were reduced but Bcl-2 expression was increased in A-H/S-H cells. The TrkB (anoikis-related) and Beclin1 (autophagy-related) levels were consistently high and low, respectively, in both A-H/S-H cells. Resistance to chemotherapy in vitro and higher capacities on tumor formation in vivo was presented in both A-H/S-H cells. PI3K/AKT/mTOR pathway components, PIK3CA, PIK3CD, AKT3, ECM1, GPCR, mTOR and PRKCB were increased but that the Nur77 and PTEN were decreased in A-H/S-H cells, identified by RNA-Seq and consistently confirmed by RT-PCR and Western blot analyses.
Heterogeneous cell subpopulations exhibiting distinct invasive and migratory capacities co-exist within the SKOV3 and A2780 cell lines. PI3K/AKT/mTOR pathway activation is associated with higher invasive and migratory capacities in subpopulations of human ovarian cancer cell lines. Inhibiting this pathway may be useful for the chemoprevention or treatment of EOC.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate the effects of salvage chemotherapy on recurrent or persistent ovarian clear cell carcinoma (CCC) with the goal of identifying a more rational treatment regimen for this lethal disease.The medical records of patients with CCC were retrospectively reviewed to select patients that were subsequently treated for recurrent or persistent disease.Of the 164 women with recurrent or persistent CCC, 485 chemotherapy courses with 1766 cycles were administered. Overall, the clinical benefit rate (CBR) was 39.4%, and the mean progression-free survival (PFS) was 4.5 months. Grade 3/4 toxicities occurred in 94 courses (19.4%). The CBR for TC was 45.1%, with a PFS of 3.7 months. Compared to that of TC, the CBRs for PC and CC were significantly lower (P = 0.020 and 0.021, respectively). The CBRs and PFS for PAF-C were slightly higher (P = 0.518 and 0.077, respectively), but showed a significantly higher adverse event rate (AER, P = 0.039). The CBR for bevacizumab was 50% with an extraordinarily long PFS (49.8 months). Gemcitabine and oxaliplatin had similar values for CBRs (44.4% and 44.1%) and PFS (2.5 and 3.4 months), respectively. Docetaxel (weekly) exhibited a notably low AER of 2.7%, and topotecan was associated with a relatively long PFS (7.7 months).For cis/carboplatin-pretreated patients, the existing active agents, such as oxaliplatin, gemcitabine, topotecan, and especially bevacizumab, are promising. Docetaxel (weekly) is well tolerated and might offer a particularly viable option for heavily pretreated patients. However, additional research to identify for a continued search for the optimal combination of chemotherapeutics or novel agents is still warranted.
Medicine 07/2015; 94(27):e1121. DOI:10.1097/MD.0000000000001121 · 5.72 Impact Factor
International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 06/2015; 130(3). DOI:10.1016/j.ijgo.2015.03.042 · 1.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the benefits of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) in patients undergoing secondary cytoreductive surgery (SCRS) for recurrent epithelial ovarian cancer.
Patients were identified and their clinical information was extracted by review of the gynaecologic oncology database of our hospital. 18F-FDG-PET scan and analysis were performed by nuclear medicine experts at our hospital.
The PET group and the control group of patients evaluated by conventional imaging methods differed significantly with respect to the proportion of patients who underwent complete SCRS and the number of residual lesions (P=0.002 and 0.006, respectively). A Cox model showed that longer progression-free survival (PFS) correlated significantly with 18F-FDG-PET evaluation (RR=0.432, P=0.001), sensitivity to platinum-based chemotherapies (RR=0.604, P=0.034), and resection completeness (RR=0.679, P=0.039). Longer overall survival correlated significantly with sensitivity to platinum-based chemotherapy (RR=0.317, P=0.000) and the CA-125 level after two cycles of chemotherapy (RR=2.663, P=0.003). Surgical safety and complications did not significantly differ between the two groups of patients.
18F-FDG-PET is useful for evaluating patients with recurrent epithelial ovarian carcinoma. Patients who undergo PET-guided SCRS have a greater chance of complete tumour resection and a longer PFS. Advances in knowledge: Secondary cytoreductive surgery guided by PET results in fewer residual lesions. PET-guided secondary cytoreductive surgery is safe and can prolong PFS and OS in patients with recurrent ovarian cancer.
The British journal of radiology 05/2015; 88(1052):20150109. DOI:10.1259/bjr.20150109 · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study aimed to establish a nomogram by combining clinicopathologic factors with overall survival of stage IA-IIB cervical cancer patients after complete resection with pelvic lymphadenectomy.
This nomogram was based on a retrospective study on 1,563 stage IA-IIB cervical cancer patients who underwent complete resection and lymphadenectomy from 2002 to 2008. The nomogram was constructed based on multivariate analysis using Cox proportional hazard regression. The accuracy and discriminative ability of the nomogram were measured by concordance index (C-index) and calibration curve.
Multivariate analysis identified lymph node metastasis (LNM), lymph-vascular space invasion (LVSI), stromal invasion, parametrial invasion, tumor diameter and histology as independent prognostic factors associated with cervical cancer survival. These factors were selected for construction of the nomogram. The C-index of the nomogram was 0.71 (95% CI, 0.65 to 0.77), and calibration of the nomogram showed good agreement between the 5-year predicted survival and the actual observation.
We developed a nomogram predicting 5-year overall survival of surgically treated stage IA-IIB cervical cancer patients. More comprehensive information that is provided by this nomogram could provide further insight into personalized therapy selection.
Asian Pacific journal of cancer prevention: APJCP 05/2015; 16(9):3773-7. DOI:10.7314/APJCP.2015.16.9.3773 · 2.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Owing to the rarity of sex cord tumor with annular tubules (SCTAT), it is difficult to recognize SCTAT clinically and there is no standard treatment. The aim of our study was to investigate the treatment outcomes and prognosis of patients with ovarian SCTAT.
A cohort of 13 patients with SCTAT diagnosed and treated in Peking Union Medical College Hospital was studied. Data on clinicopathological characteristics, treatment, and prognosis were retrospectively reviewed and analyzed.
SCTAT accounted for 1.4% of ovarian sex cord stromal tumors, with an average onset age of 22.6 years. All patients presented with menstrual disturbances or isosexual precocity at disease onset. Initial surgery was unilateral salpingo-oophorectomy in 11 cases. Recurrence rate was 46.2%, and 38.5% of patients experienced multiple recurrences. The disease free interval gradually shortened with increasing numbers of recurrences. Recurrent tumors were mostly ipsilateral to the primary tumor and located in retroperitoneum. Surgery remained the main treatment for recurrent cases. Serum estradiol and progesterone levels usually elevated at disease onset, decreased dramatically after operation, and they elevated again with the development of recurrence. The median progression-free survival (PFS) was 97.8 months, and the 1-year and 5-year PFS were 92% and 67%, respectively. Five-year overall survival (OS) was 100%.
Unilateral salpingo-oophorectomy is a feasible treatment for primary SCTAT cases with intact capsules and without PJS. Complete tumor resection is suggested for recurrent cases and long-term follow-up is strongly recommended. Despite the high risk of recurrence, SCTAT prognosis is relatively favorable.
BMC Cancer 04/2015; 15(1):270. DOI:10.1186/s12885-015-1277-y · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To profile the characteristic and prognostic implications of venous thromboembolism (VTE) in Chinese ovarian clear cell carcinoma (CCC) patients.
We identified all of the cases between 2000 and 2012 by searching our institutional Ovarian CCC Database. A comprehensive review of the medical documentation was performed to collect relevant data. Kaplan-Meier models and Cox regression were employed for survival analysis.
Of the 227 patients, 33 (14.5%) experienced VTE events. There was no significant difference between VTE and non-VTE group patients regarding age, serum cancer antigen 125 or tumor size. The optimal cytoreduction rate was higher in patients without VTE (70.1%) than in those with VTE (51.5%). VTE events were more likely to occur at presentation (36.4%) and recurrence (33.3%), followed by an adjuvant chemotherapy period (18.2%). VTE was more common in patients with advanced-stage disease than those with early-stage disease (P=0.003), whereas pulmonary embolism (PE) was 10-fold as common in advanced-stage disease as in early-stage disease (8.6% vs. 0.8%, P = 0.012). Patients with advanced disease tended to have thrombi in the proximal veins. Two patients died of PE, as confirmed by autopsy. Patients with VTE had reduced survival compared to those without VTE (median overall survival 54 vs. 140 months, P<0.001; median progression-free survival 17 vs. 43 months, P<0.001).
Overall, 14.5% of the patients with ovarian CCC experienced VTE, mainly before their cancer diagnosis or at a time of recurrence. VTE adversely impacted patient survival.
PLoS ONE 03/2015; 10(3-3):e0121818. DOI:10.1371/journal.pone.0121818 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the study reported here was to investigate the protective effect of gonadotropin-releasing hormone analog (GnRHa) against cyclophosphamide (CTX)-induced gonadotoxicity.
Eighty Fischer 344 rats were divided randomly into four groups (20 per group). One group received normal saline, one GnRHa, one CTX, and one GnRHa+CTX. Several parameters were used to observe the ovarian reserve, including ovary weight, follicle number and diameter, concentrations of estradiol (E2) and follicle-stimulating hormone (FSH), and expressions of sex hormone receptors.
When treatment was finished, the number of small follicles in the GnRHa+CTX group was significantly higher than in the CTX-alone group. Thirty days after treatment, the ovary weight, percentage of small follicles, mean follicular diameter, and serum concentrations of E2 and FSH in the GnRHa+CTX group all recovered, approaching normal levels. Sex hormone receptors did not show significant differences between the four groups.
Combination treatment with GnRHa could prevent CTX-induced damage to ovarian reserve.
OncoTargets and Therapy 03/2015; 8:661-7. DOI:10.2147/OTT.S78729 · 2.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Induction of cell apoptosis and regulation of cell cycle are very attractive for treatments of tumors including ovarian carcinoma. Flavopiridol is a potent small molecular cyclin-dependent kinase(cdk) inhibitor, but its antitumor efficacy is not satisfied yet. Caspase-3 play a major role in the transduction of apoptotic signals and the execution of apoptosis in mammalian cells.We have successfully constructed the recombinant adenovirues AdHTVP2G5-rev-casp3 containing autocatalytic caspase-3 (rev-caspase-3) driven by amplified hTERT promoter system (TSTA-hTERTp). In this study, we applied it with flavopiridol to investigate their antitumor effect on ovarian cancer in vitro and in vivo.Methods
Cell viabilities were determined using Cell Counting Kit 8 and flow cytometry. RT-PCR and immunoblotting assays were used to detect cellular apoptotic activities. Tumor growth and survival of mice bearing tumors were studied.ResultsFlavopiridol or AdHTVP2G5-rev-casp3 at low dosage alone was mildly cytotoxic in vitro with a viability rate of 86.5¿±¿4.7% for 300 nM flavopiridol and 88.9¿±¿5.4% for AdHTVP2G5-rev-casp3 (MOI 20). By contrast, significant synergism of their sequential combination was observed, and the treatment of AdHTVP2G5-rev-casp3 (MOI 20) infection for 72 h, followed by flavopiridol(300nM) for 48 h, can result in the most synergistic cell death, with cell survival rate and apoptotic rate of 11.6% and 69.7%, respectively. The sequential combination showed synergistic tumor suppression rate of 77.8%, which was significantly higher than that of AdHTVP2G5-rev-casp3 (33.6%) or flavopiridol (40.1%) alone. The mean survival of mice treated with the combination was 286¿±¿8d, which was synergistically longer than that of mice treated with AdHTVP2G5-rev-casp3 (141¿±¿14d), flavopiridol (134¿±¿10d) or controls (106¿±¿11d) (P¿<¿0.01).Conclusions
The sequential combination of rev-caspase-3 and flavopiridol result in significant synergistic cell killing effects, significant tumor growth suppression and extended survival of mice bearing OVCAR3 cells. The combination should be further explored as a potential clinically useful regimen against ovarian cancer.
Journal of Ovarian Research 12/2014; 7(1):121. DOI:10.1186/PREACCEPT-1575959814127936 · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of our study is to investigate the differences in therapeutic effects and clinical significance between intravenous systematic chemotherapy and intra-arterial interventional chemotherapy in stage Ib2-IIb cervical carcinomas.
A retrospective analysis was performed on 93 cases of intravenous and 118 cases of intra-arterial neoadjuvant chemotherapy for stage Ib2-IIb cervical carcinomas treated in Peking Union Medical College Hospital from the year 2001 to 2010.
After neoadjuvant chemotherapy, the overall response rate was 84.9% versus (vs) 88.2% and the operability rate was 77.4% vs 81.4%, for intravenous vs intra-arterial (P>0.05). There were no significant differences in toxicities, surgical duration, perioperative blood loss, and operative complications between these two groups. Postoperative pathological examination revealed a significantly lower parametrial infiltration in the intra-arterial group (12.5% vs 38.1%, P<0.05), while the positive vaginal margin, lymph node metastasis, and intravascular tumor embolus showed no significant differences. The intravenous group and the intra-arterial group had similar recurrence rate (16.0% vs 12.3%), distant metastasis rate (9.1% vs 8.5%), and 5 year survival rate (79.5% vs 84.9%), without significant differences.
Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil are safe and effective for patients with locally advanced cervical carcinomas. The intravenous and the intra-arterial approaches present with similar chemotherapy efficacy and clinical outcome. Since it is more simple and economical, the intravenous systematic approach shows greater value in clinical application.
OncoTargets and Therapy 11/2014; 7:2155-2160. DOI:10.2147/OTT.S67633 · 2.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Radical vaginal trachelectomy (VRT) is widely prescribed as a surgical procedure to treat early-stage cervical cancer while preserving fertility. However, the ideal obstetric standard of care for patients who have undergone VRT has not yet been established. Aim of this rerport is to analyze pregnancy outcomes and optimal obstetric management during pregnancy and delivery after vaginal radical trachelectomy (VRT).
Patients and methods:
Forty-six cases of VRT from December 2003 to April 2013 in Peking Union Medical College Hospital were analyzed.
The mean age of the patients at the time of VRT was 30.6 years and the mean follow-up time was 39.5 months. Of the 32 patients who attempted to conceive, 12 had 16 successful conceptions. There were two miscarriages and two elective abortions. One case of ectopic pregnancy and one case of second trimester loss occurred in this cohort. Ten cases reached the third trimester. Two patients delivered before 32 weeks, and four before 37 weeks. The total preterm delivery rate was 60%. All ten patients delivered by Cesarean section through a high transverse uterine incision. No uterine rupture or postpartum hemorrhage occurred.
There is an increased occurrence of preterm delivery after VRT. Cesarean section after full term pregnancy through a high transverse incision should be considered as a suitable and safe procedure.
[Show abstract][Hide abstract] ABSTRACT: Purpose
To investigate tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group (PcG) proteins.
Tissue microarrays containing matched primary and recurrent ovarian tumors from the same patients were constructed for detection of PcG protein expression. Survival analyses of clinicopathological parameters and expression of PcG proteins were performed on progression-free survival (PFS) and overall survival (OS) of patients. Genetic and epigenetic heterogeneity was explored in aspects of gene copy number and microRNA (miRNA) profiling.
PcG proteins were heterogeneously expressed in primary versus recurrent tumors (P<0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of BMI1 and EZH2 in first-onset lymph node metastases with shortened PFS was demonstrated (P=0.010, P=0.019); and a significant association of intensive expression of BMI1 and EZH2 in recurrent tumors with shortened OS was demonstrated (P=0.042, P=0.047). Importantly, BMI1 and EZH2 expression provided significant independent prognostic parameters in multivariate analyses (P<0.05). Gene amplification did not always coincide with PcG protein expression. Eight miRNAs were found to be downregulated in recurrent tumors, among which miR-298 might indirectly regulate the expression of EZH2 through transcription factor ILF3.
Tumor heterogeneity exists in the recurrence of epithelial ovarian cancer, manifested by PcG protein expression and underlying genetic and epigenetic alterations. Intensive expression of BMI1 and EZH2 are predictors of earlier relapse and shorter OS, independent of grade and chemotherapy sensitivity. EZH2 and miR-298 have great potential to be new targets for treatment of recurrent ovarian cancer.
OncoTargets and Therapy 09/2014; 7:1705-16. DOI:10.2147/OTT.S67570 · 2.31 Impact Factor