Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer.

Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the bric-a-brac-tramtrack-broad complex/pox virus and zinc finger gene family, is known to serve important roles in the proliferation and growth of tumor cells, and in chemotherapy resistance. However, the underlying molecular mechanisms through which NAC1 contributes to drug resistance remain unclear. In the present study, the role of NAC1 in drug resistance in ovarian cancer was investigated. NAC1 expression was markedly negatively associated with growth arrest and DNA-damage-inducible 45γ-interacting protein 1 (GADD45GIP1) expression in ovarian cancer. Increased NAC1 expression or decreased GADD45GIP1 expression was significantly associated with decreased progression-free survival (P=0.0041). Multivariate analysis demonstrated that NAC1/GADD45GIP1 expression was an independent prognostic factor of progression-free survival (P=0.0405). It was investigated whether cellular senescence was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. Treatment with cisplatin activated cellular senescence in ovarian cancer cell lines (SKOV3 and TOV-21G cells). Furthermore, knockdown of NAC1 by RNA interference significantly increased GADD45GIP1 expression and inhibited cisplatin-induced cellular senescence, resulting in increased cisplatin cytotoxicity in SKOV3 cells, which express increased levels of NAC1. To investigate whether the sensitizing effect of NAC1 inhibition on cisplatin-induced cytotoxicity may be attributed to the suppression of cellular senescence, the effects of NAC1 overexpression were assessed in TOV-21G cells, which do not express endogenous NAC1. Transfection with NAC1 in TOV-21G cells reduced the sensitivity of TOV-21G cells to cisplatin, indicating that suppression of cellular senescence was induced by GADD45GP1 activation. The results of the present study suggest that NAC1 is a negative regulator of cellular senescence and that NAC1-dependent suppression of senescence, mediated through GADD45GIP1, serves an important role in promoting cisplatin resistance. Therefore, the NAC1/GADD45GIP1 axis may be a potential target for the treatment of ovarian cancer, particularly in platinum-resistant cancers.

CCNE1 amplification is associated with aggressive potential in endometrioid endometrial carcinomas.

The clinicopathological significance of amplification was investigated of the gene encoding cyclin E (CCNE1) and we assessed whether CCNE1 was a potential target in endometrioid endometrial carcinomas. CCNE1 amplification and CCNE1 or F-box and WD repeat domain-containing 7 (FBXW7) expression in endometrial endometrioid carcinoma was assessed by immunohistochemistry and fluorescence in situ hybridization. CCNE1 knockdown by small interfering RNA (siRNA) was used to assess the CCNE1 function. The results showed that CCNE1 amplification was present in 9 (8.3%) of 108 endometrial carcinomas. CCNE1 amplification was correlated with high histological grade (Grade 3; p=0.0087) and lymphovascular space invasion (p=0.0258). No significant association was observed between CCNE1 amplification and FIGO stage (p=0.851), lymph node metastasis (p=0.078), body mass index (p=0.265), deep myometrial invasion (p=0.256), menopausal status (p=0.289) or patient age (p=0.0817). CCNE1 amplification was significantly correlated with shorter progression-free and overall survival (p=0.0081 and 0.0073, respectively). CCNE1 protein expression or loss of FBXW7 expression in endometrial endometrioid carcinoma tended to be correlated with shorter progression-free and overall survival; however, this difference was not statistically significant. Multivariate analysis showed that CCNE1 amplification was an independent prognostic factor for overall survival but not for progression-free survival (P=0.0454 and 0.2175, respectively). Profound growth inhibition was observed in siRNA-transfected cancer cells with endogenous CCNE1 overexpression compared with that in cancer cells having low CCNE1 expression. CCNE1 amplification was independent of p53, HER2, MLH1 and ARID1A expression but dependent on PTEN expression in endometrial carcinomas. These findings indicated that CCNE1 amplification was critical for the survival of endometrial endometrioid carcinomas. Furthermore, the effects of CCNE1 knockdown were dependent on the CCNE1 expression status, suggesting that CCNE1-targeted therapy may be beneficial for patients with endometrial endometrioid carcinoma having CCNE1 amplification.

ESR1 gene amplification in endometrial carcinomas: a clinicopathological analysis.

This study investigated the clinicopathological significance of estrogen receptor 1 (ESR1) gene amplification and its relationship to phosphatase and tensin homolog (PTEN), human epidermal growth factor receptor 2 (HER2), MutL homolog 1 (MLH1), p53, and AT rich interactive domain 1A (ARID1A) expression in endometrial carcinomas. ESR1 amplification and expression were assessed by fluorescence in situ hybridization and immunohistochemistry. Clinical data were collected by retrospective chart review. ESR1 amplification was identified in 13 out of 111 (11.7%) endometrial carcinomas. No significant association was observed between ESR1 amplification and International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.17), histological grade (p=0.35), lymph node metastasis (p=0.51), or deep myometrial invasion (p=0.46). ESR1 amplification was independent of PTEN, p53, HER2, MLH1, and ARID1A protein expression. Patients without estrogen receptor (ER) or progesterone receptor (PR) expression had shorter progression-free and overall survival than those with ER or PR expression (p<0.01). ESR1 amplification is independent of known clinicopathological factors related to poor prognosis and PTEN, p53, HER2, MLH1, and ARID1A protein expression, suggesting ESR1 amplification may be an early event in endometrial carcinoma development.

KRAS and MAPK1 gene amplification in type II ovarian carcinomas.

In this study, we examined the clinical significance of KRAS and MAPK1 amplification and assessed whether these amplified genes were potential therapeutic targets in type II ovarian carcinoma. Using fluorescence in situ hybridization, immunohistochemistry, and retrospectively collected clinical data, KRAS and MAPK1 amplifications were identified in 9 (13.2%) and 5 (7.4%) of 68 type II ovarian carcinoma tissue samples, respectively. Interestingly, co-amplification of KRAS and MAPK1 seemed to be absent in the type II ovarian carcinomas tested, except one case. Active phospho-ERK1/2 was identified in 26 (38.2%) out of 68 type II ovarian carcinomas and did not correlate with KRAS or MAPK1 amplification. There was no significant relationship between KRAS amplification and overall or progression-free survival in patients with type II ovarian carcinoma. However, patients with MAPK1 amplification had significantly poorer progression-free survival than patients without MAPK1 amplification. Moreover, type II ovarian carcinoma cells with concomitant KRAS amplification and mutation exhibited dramatic growth reduction following treatment with the MEK inhibitor PD0325901. These findings indicate that KRAS/MAPK1 amplification is critical for the growth of a subset of type II ovarian carcinomas. Additionally, RAS/RAF/MEK/ERK pathway-targeted therapy may benefit selected patients with type II ovarian carcinoma harboring KRAS/MAPK1 amplifications.

A Case of Stage III c Ovarian Clear Cell Carcinoma: The Role for Predictive Biomarkers and Targeted Therapies.

Ovarian cancer treatment presently does not reflect molecular differences in histologic subtype. Ovarian clear cell carcinoma (OCCC) exhibits several differences in terms of molecular pathogenesis and tumor behavior from the more common, chemosensitive, serous carcinomas, which makes OCCC a candidate for targeted therapies. A 53-year-old Japanese woman was diagnosed with stage IIIc ovarian clear cell adenocarcinoma with marked chemoresistance to conventional regimens. She demonstrated a partial response to a multikinase inhibitor. The tumor was resistant to PI3K/mTOR pathway inhibitors despite harboring a PIK3CA mutation. The present case suggests a role for targeted therapies in the treatment of OCCC and a need for the identification of biomarkers that will predict response to targeted therapies.

Fatty acid synthase is a potential therapeutic target in estrogen receptor-/progesterone receptor-positive endometrioid endometrial cancer.

OBJECTIVE: In the current study we investigated the clinicopathological significance of fatty acid synthase (FASN) expression and its relationship with estrogen receptor (ER) and progesterone receptor (PR) in endometrioid endometrial cancer. METHODS: FASN expression in endometrioid endometrial cancer was assessed by immunohistochemistry using 108 paraffin-embedded tissue specimens and clinical data collected from a retrospective chart review. The specific FASN inhibitor C75 was used to analyze the relationship between FASN expression and cell growth as well as ER/PR expression in endometrioid endometrial cancer cell lines. RESULTS: Positive FASN immunostaining was observed in 77.8% (84/108) of the tumors analyzed. Deep myometrial invasion was significantly and inversely correlated with positive FASN expression (p = 0.024). Positive ER (p = 0.018) and PR status (p = 0.012) was significantly correlated with positive FASN expression. Patients with positive FASN expression in endometrioid endometrial cancer tissues tended to have a favorable progression-free/overall survival (p = 0.127 and p = 0.087, respectively). Ishikawa cells with high FASN expression also showed high expression of ER/PR, while HEC1B cells had low expression levels of both FASN and ER/PR. FASN inhibition by C75 (10 µM) significantly reduced ER/PR expression compared with control dimethyl sulfoxide treatment of Ishikawa cells. The growth of Ishikawa cells having positive FASN and ER/PR expression was significantly inhibited in the presence of C75 or FASN small-interfering RNA compared to HEC1B cells that lacked FASN and ER/PR expression. CONCLUSION: The current findings suggest that there may be cross talk between the ER/PR and FASN signaling pathways that modulate ER/PR activation and could play a role in endometrioid endometrial cancer pathogenesis.

PPP2R1A mutation is a rare event in ovarian carcinoma across histological subtypes.

Somatic mutations in PPP2R1A, which encodes a scaffolding subunit of serine/threonine protein phosphatase 2A (PP2A), have recently been described in different types of gynecological neoplasias. To extend this observation, we examined the frequency of PPP2R1A mutation in some major histological subtypes of type I and type II ovarian carcinoma. Mutational analysis of PPP2R1A (exons 5 and 6) was performed on 88 primary ovarian carcinomas, including mucinous, clear cell, high-grade serous, and high-grade endometrioid ovarian carcinoma. In addition, exons 9 and 20 of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), exon 1 of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), and exon 15 of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) were sequenced and compared across the different histological subtypes. Finally, survival analysis was performed to determine any prognostic significance of these mutations. Mutations in PPP2R1A were rare: detected in 4.5% (1/22) of clear cell, 4.5% (1/22) of high-grade serous, and 6.7% (1/15) of high-grade endometrioid ovarian carcinoma. Interestingly, no PPP2R1A mutations were observed in mucinous ovarian carcinoma. A higher frequency of PIK3CA mutations (50%, 11/22) was found in clear cell carcinoma and a higher frequency of KRAS mutations (24.1%, 7/29) was observed in mucinous carcinoma. In addition, high-grade endometrioid ovarian carcinoma exhibited KRAS and PIK3CA mutations in 26.7% (4/15) and 20% (3/15) of cases, respectively. Survival analysis showed no significant association between mutational status and overall survival of patients. This study indicates that the PPP2R1A mutation occurs at a lower frequency compared to other gynecological malignancies, irrespective of the histological subtype.

Clinicopathologic analysis of loss of AT-rich interactive domain 1A expression in endometrial cancer.

Loss of the AT-rich interactive domain 1A (a putative tumor suppressor) protein BAF250a has recently been described as a frequent event in endometrial carcinoma. In this study, we determined the significance of the loss of AT-rich interactive domain 1A immunoreactivity for several clinicopathologic features of uterine endometrioid carcinoma. AT-rich interactive domain 1A expression was assessed by immunohistochemistry using 111 paraffin-embedded tissue specimens and clinical data collected by a retrospective medical record review. The correlations between loss of AT-rich interactive domain 1A protein and clinicopathologic and prognostic features were examined. In addition, the expression of PTEN, p53, Her2, and MLH1 was assessed by immunohistochemistry and compared with AT-rich interactive domain 1A expression. AT-rich interactive domain 1A immunoreactivity was undetectable in 27 (24%) of 111 analyzed endometrioid endometrial carcinomas. There was no significant difference between negative and positive cases of AT-rich interactive domain 1A in terms of any clinicopathologic features examined (International Federation of Gynecology and Obstetrics stage, grade, depth of myometrial invasion, lymph node metastasis, lymphovascular space invasion, body mass index, postmenopausal status, patient age at diagnosis, and estrogen and progesterone receptor status). The comparison between the expression of AT-rich interactive domain 1A and the expression of PTEN, p53, Her2, and MLH1 also revealed no significant association. There was no significant correlation between AT-rich interactive domain 1A expression and progression-free/overall survival of patients. This study provides the first examination of the clinicopathologic relationship between AT-rich interactive domain 1A protein expression and endometrial carcinoma. No significant differences between positive and negative cases of AT-rich interactive domain 1A were observed with respect to any clinicopathologic features or patient survival.

Is ATP7B a predictive marker in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy?

OBJECTIVE: This study examined the prognostic significance of copper-transporting P-type adenosine triphosphatase (ATP7B) expression in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy. METHODS: Expression of ATP7B in ovarian carcinoma was assessed by immunohistochemistry and clinical data collected by retrospective review of medical charts. RESULTS: Overexpression of ATP7B was identified in 25 (29.1%) of 86 ovarian carcinomas. The frequency of ATP7B expression in clear cell carcinomas was significantly higher than that in serous high-grade carcinomas (P < 0.05). We observed no statistically significant correlations between high ATP7B protein expression and either disease-free survival (P = 0.722) or overall survival (P = 0.389). CONCLUSIONS: Our study is the first to demonstrate a lack of statistically significant differences between ATP7B positive and negative cases with respect to prognosis of patients with ovarian carcinoma treated with a platinum-taxane combination regimen. However, that ATP7B expression in clear cell carcinomas was significantly higher than that in serous carcinomas may partially explain the difference in chemotherapeutic response and prognosis between patients with these 2 types of carcinomas.

Notch3 overexpression as potential therapeutic target in advanced stage chemoresistant ovarian cancer.

This study examined the clinical significance of Notch3 expression and assessed its usefulness as a potential therapeutic target in chemoresistant ovarian cancer. Notch3 expression was assessed with immunohistochemical examination, and clinical variables were collected with a retrospective chart review. Notch3 siRNA or γ-secretase inhibitor was used to assess Notch3 function in ovarian cancer cell lines. Notch3 overexpression correlated with shorter progression-free/overall survival in patients with advanced stage (stage III, IV) ovarian carcinoma treated with platinum and taxane. Three of 5 patients showed increased Notch3 immunostaining in recurrent tumors compared with corresponding primary tumors. Notch3 overexpression was observed in both the cisplatin-resistant KFr13 and cisplatin/paclitaxel-resistant KFr13Tx cells. Inactivation of Notch3 by γ-secretase inhibitor or siRNA decreased cell proliferation and induced apoptosis in the KFr13 and KFr13Tx cells. Our findings suggest that Notch3 expression may be related to chemoresistance and that the Notch3 pathway may represent a novel therapeutic target for advanced stage chemoresistant ovarian cancer.

NAC1, a BTB/POZ protein overexpressed in uterine sarcomas.

BACKGROUND: The purpose of this study was to investigate the role of Nucleus accumbens-associated 1 (NAC1) in the development of uterine sarcomas. MATERIALS AND METHODS: NAC1 expression and localization in the normal myometrium, benign leiomyoma, and uterine sarcoma were assessed with immunohistochemistry. NAC1-specific siRNA was used to inactivate NAC1 for in vitro biological assays. RESULTS: Almost all cases of uterine sarcoma were found to overexpress NAC1. Expression of NAC1 was significantly higher in uterine sarcomas than in benign leiomyomas (p<0.0001). NAC1 gene knockdown inhibited cell growth and induced apoptosis in SKN, a leiomyosarcoma cell line, and in OMC-9, an endometrial stromal sarcoma cell line, both of which overexpress NAC1. CONCLUSION: Uterine sarcomas with NAC1 overexpression are clinically the most aggressive, chemoresistant, and radioresistant tumors. Therefore, detection of NAC1 overexpression in uterine sarcomas may identify patients who will benefit from NAC1-targeted therapy.

Gene amplification of ZNF217 located at chr20q13.2 is associated with lymph node metastasis in ovarian clear cell carcinoma.

BACKGROUND: Recently we reported that amplification of the Zinc Finger Protein 217 (ZNF217) gene adversely affects survival of patients with ovarian clear cell carcinoma. This study sought to determine the mechanism by which ZNF217 amplification affects patient survival. MATERIALS AND METHODS: Fluorescence in situ hybridization (FISH) was used to detect ZNF217 gene amplification status and ZNF217-specific siRNA was used to inactivate ZNF217 for in vitro biological analyses. RESULTS: We found ZNF217 gene amplification to be significantly correlated with lymph node metastasis (p<0.05) in ovarian clear cell carcinoma. Profound inhibition of cell migration and invasion was observed in siRNA-treated cells with ZNF217 amplification, compared to cells without amplification. CONCLUSION: These findings provide new insight into the biological role of ZNF217 gene amplification in ovarian clear cell carcinoma. Additionally, our observations have an important therapeutic implication for patients with ovarian clear cell carcinomas with ZNF217 amplification, as these patients may potentially benefit from ZNF217 targeted-therapy.

Clinicopathologic and biological analysis of PIK3CA mutation in ovarian clear cell carcinoma.

Somatic mutations of PIK3CA (phosphoinositide-3-kinase) have recently been shown playing an important role in the pathogenesis of ovarian clear cell carcinoma. In this study, the frequency of PIK3CA mutations and the relationship of PIK3CA mutations with clinicopathologic and biological variables were investigated in ovarian clear cell carcinomas from Japanese patients. Mutational analysis of PIK3CA was performed in 56 primary ovarian clear cell carcinomas from Japanese women. The relationship of these mutations with various clinicopathologic and biological variables (phosphorylated AKT and phosphorylated mTOR (mammalian target of rapamycin) expression by immunohistochemistry) was determined. To clarify the roles of PI3K/AKT activation in ovarian clear cell carcinomas harboring PIK3CA mutations, we inactivated the PI3K/AKT/mTOR pathway in ovarian carcinoma cells with LY294002, temsirolimus and NVP-BEZ235. Missense mutations of PIK3CA were found in 16 (28.6%) of 56 ovarian clear cell carcinomas, but no mutation was found in 15 ovarian high-grade serous carcinomas. PIK3CA mutations were significantly associated with a favorable overall survival of patients with ovarian clear cell carcinoma (P < .05). There was no significant association between PIK3CA mutations and phosphorylated AKT or phosphorylated mTOR immunointensity status. No relationship was found between PIK3CA mutation status and sensitivity to PI3K/AKT/mTOR inhibitors in ovarian clear cell carcinoma cells. No association of PIK3CA mutations was found between positive phosphorylated AKT and positive phosphorylated mTOR, which suggests that the PI3K/AKT/mTOR pathway may be activated by other molecular mechanisms. Although PIK3CA mutations were associated with a more favorable prognosis, they did not predict the sensitivity of ovarian clear cell carcinoma cells to PI3K/AKT/mTOR inhibitors.

Sister Mary Joseph's nodule associated with rare endometrial squamous cell carcinoma.

BACKGROUND: Umbilical metastasis (Sister Mary Joseph's nodule) is a rare physical sign seen only in 1-3 % of patients with an intra-abdominal and/or pelvic malignancy. Here, we present a case of Sister Mary Joseph's (SMJN) nodule originating from a primary squamous cell carcinoma of the endometrium, a rare histological subtype. CASE HISTORY: SMJN was detected in a 30-year-old woman after a preoperative CT scan for a suspected umbilical hernia. Subsequent laparotomy and histopathological examination confirmed endometrial squamous cell carcinoma metastasizing to the umbilical region. CONCLUSION: The SMJN may be the first presenting sign of an intra-abdominal and/or pelvic malignancy and may co-exist with an umbilical hernia. Therefore, malignancy should be considered one of the differentials of an umbilical mass.

[A case of stage IVb cervical carcinoma in which survival was prolonged by two different chemotherapies and CCRT].

Pulmonary metastasis from primary cervical carcinoma is rare, with an incidence of 4.16-7.7%. Chemotherapy is the most common treatment; however, the overall prognosis is poor. This case report describes a complete response to CCRT and TC therapy of cervical carcinoma metastatic to the lung. The patient, a 57-year-old woman, was initially diagnosed with FIGO clinical Stage IVb cervical carcinoma with lung metastasis, after presenting with vaginal bleeding. She had a 90 pack/year smoking history. She was initially treated with systemic chemotherapy(TC therapy: PTX, CBDCA 1 course)followed by concurrent chemoradiotherapy(CCRT)with weekly CDDP2 0mg/m2. She had a complete response of her pelvic disease as well as a decrease in the size of metastatic lesions. Following CCRT, she was scheduled to continue TC therapy, but was only able to complete two courses secondary to a myocardial infarction. A lung biopsy at that time showed no evidence of malignancy, and the patient has remained without any evidence of disease for the past six years.

Uterine leiomyosarcoma producing granulocyte colony stimulating factor.

Uterine leiomyosarcoma associated with the paraneoplastic production of granulocyte-colony stimulating factor (GCSF) is extremely rare. No case has been reported to date in the English literature. We describe a case of a 56-year-old female with recurrent uterin leiomyosarcoma, associated with leukocytosis (19100/mm) and an elevated serum GCSF (33.0 pg/ml). Tumore histology was consistent with a well differentiated leiomyosarcoma with marked neutrophilic infiltration of the lung and spleen metastases. tumor cells were distinctly positive for GCSF on immunohistochemistry. These findings confirmed the diagnosis of a GCSF-producting uterine leiomyosarcoma with a paraneoplastic leukocytosis.

Frequent loss of tumor suppressor ARID1A protein expression in adenocarcinomas/adenosquamous carcinomas of the uterine cervix.

OBJECTIVES: Expression of ARID1A (the adenine, thymine-rich interactive domain 1A), a putative tumor suppressor, has recently been shown to be lost in several tumor types. This study investigated whether ARID1A expression was also lost in cervical squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas. METHODS: A total of 91 patients with cervical carcinoma were enrolled. Cervical carcinoma specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, and prognosis were investigated. RESULTS: Using immunohistochemistry, the frequency of loss of ARID1A expression in adenocarcinomas/adenosquamous carcinomas (31.1% [14/45]) was significantly higher than that in squamous cell carcinomas (6.5% [3/46]; P = 0.0017). There was no significant association between the loss of ARID1A expression and International Federation of Gynecology and Obstetrics staging, lymphovascular space invasion, lymph node metastasis, age, and Ki-67 LI in cervical adenocarcinomas/adenosquamous carcinomas. Loss of ARID1A expression was not correlated with shorter overall/disease-free survival in cervical adenocarcinomas/adenosquamous carcinomas. CONCLUSIONS: In conclusion, this study provides the first evidence of the frequent loss of ARID1A protein expression in cervical adenocarcinomas/adenosquamous carcinomas. No significant differences between ARID1A positive and negative cases were observed with respect to any clinicopathological features examined.

Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma.

Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma. A total of 60 patients, who were surgically treated for primary ovarian clear cell adenocarcinoma, were enrolled. Surgical specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, prognosis, and chemosensitivity were investigated. Loss of ARID1A expression was identified in 9 (15.0%) of 60 ovarian clear cell carcinoma samples. Loss of ARID1A staining intensity (0+) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (P<0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P=0.02, 0.01). There were no significant correlations between loss of ARID1A expression and patient age, status of residual tumor, Ki-67 labeling index, or the status of endometriosis. Loss of ARID1A correlated with shorter progression-free survival of patients with clear cell carcinomas treated with platinum-based chemotherapy (P<0.01). Loss of ARID1A expression tended to correlate with shorter overall survival in patients with ovarian clear cell carcinomas treated with platinum-based chemotherapy. When data were stratified for the multivariate analysis, only the loss of ARID1A expression remained a significant (P=0.03) predictor of reduced progression-free survival. Of the 60 patients with ovarian clear cell carcinomas, 14 patients had measurable residual tumor after primary cytoreductive surgery. Tumors with loss of ARID1A expression were more likely to be chemoresistant than tumors with positive ARID1A expression (100.0 vs 40.0%, P=0.04). This study demonstrates that loss of ARID1A in ovarian clear cell carcinoma is a negative prognostic factor in patients treated with platinum-based chemotherapy. Measurement of ARID1A expression may be a method to predict resistance to platinum-based chemotherapy in patients with ovarian clear cell carcinoma.

Biological and clinical significance of NAC1 expression in cervical carcinomas: a comparative study between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas.

This study examined the biological and clinical significance of NAC1 (nucleus accumbens associated 1) expression in both cervical squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas. Using immunohistochemistry, the frequency of positive NAC1 expression in adenocarcinomas/adenosquamous carcinomas (31.0%; 18/58) was significantly higher than that in squamous cell carcinomas (16.2%; 12/74) (P = .043). NAC1 gene amplification was identified by fluorescence in situ hybridization in 5 (7.2%) of 69 squamous cell carcinomas. NAC1 amplification was not identified in the adenocarcinomas (0%; 0/58). Positive NAC1 expression was significantly correlated with shorter overall survival in squamous cell carcinomas (P < .0001). A multivariate analysis showed that positive NAC1 expression in squamous cell carcinomas was an independent prognostic factor for overall survival after standard radiotherapy (P = .0003). In contrast to squamous cell carcinomas, positive NAC1 expression did not correlate with shorter overall survival in adenocarcinomas/adenosquamous carcinomas (P = .317). Profound growth inhibition, increased apoptosis, decreased cell proliferation, and decreased cell migration and invasion were observed in silencing RNA-treated cancer cells with NAC1 overexpression compared with cancer cells without NAC1 expression. NAC1 overexpression stimulated proliferation, migration, and invasion in the cervical cancer cell lines TCS and Hela P3, which normally lack NAC1 expression. These findings indicate that NAC1 overexpression is critical to the growth and survival of cervical carcinomas irrespective of histologic type. Furthermore, they suggest that NAC1 silencing RNA-induced phenotypes depend on the expression status of the targeted cell line. Therefore, cervical carcinoma patients with NAC1 expression may benefit from a targeted therapy irrespective of histologic type.

Prognostic and therapeutic impact of the chromosome 20q13.2 ZNF217 locus amplification in ovarian clear cell carcinoma.

BACKGROUND: The goal of this study was to examine the clinical significance of ZNF217 amplification and assess whether ZNF217 could be a potential therapeutic target in ovarian clear cell carcinoma (OCCC). METHODS: ZNF217 expression and amplification in OCCC was assessed by immunohistochemistry, fluorescence in situ hybridization, and clinical data collected via a retrospective chart review. ZNF217 gene knockdown using silencing RNA (siRNA) was used to assess ZNF217 functions in OCCC cell lines. RESULTS: Gene amplification was identified in 12 of 60 (20.0%) OCCCs. ZNF217 copy number correlated significantly with ZNF217 protein expression (r = 0.341; P<.01). ZNF217 amplification correlated significantly with shorter progression-free (P = .0042) and overall (P = .0199) survival. There were nonsignificant trends between high ZNF217 protein expression and poor progression-free (P = .2594) and overall (P = .2199) survival. Multivariate analysis revealed ZNF217 gene amplification to be an independent prognostic factor for progression-free and overall survival after standard platinum agent-based chemotherapy (P = .0339 and P = .031, respectively). Profound growth inhibition and apoptosis were observed in ZNF217 siRNA-treated cancer cells with gene amplification compared with cancer cells with ZNF217 moderate expression without ZNF217 gene amplification or with low ZNF217 expression. CONCLUSION: These findings indicate that ZNF217 overexpression is critical to growth and survival of OCCCs with ZNF217 gene amplification. Furthermore, they suggest that ZNF217 siRNA-induced phenotypes depend on amplification status of OCCCs. Therefore, ZNF217-targeted therapy may benefit OCCC patients with ZNF217 amplification.