BAF250a Expression in Atypical Endometriosis and Endometriosis-Associated Ovarian Cancer

2016 ◽  
Vol 26 (5) ◽  
pp. 825-832 ◽  
Author(s):  
John P. Stamp ◽  
C. Blake Gilks ◽  
Martine Wesseling ◽  
Sima Eshragh ◽  
Kathy Ceballos ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Nuclear Protein ◽  
Clear Cell ◽  
Early Event ◽  
Cancer Subtypes ◽  
Ovarian Cancers ◽  
Pathology Reports ◽  
Pathology Review ◽  
Atypical Endometriosis ◽  
Expression Loss

Background and ObjectiveAtypical endometriosis (AE) is thought to be a precursor lesion to the ovarian cancer subtypes associated with endometriosis, namely, endometrioid and clear cell carcinomas.ARID1Aencodes a nuclear protein (BAF250a) governing chromatin remodeling, and mutations inARID1Ahave been found in 30% to 50% of clear cell and endometrioid ovarian cancers. As BAF250a expression loss by immunohistochemistry (IHC) has been documented in the endometriosis precursor lesions closely associated with these ovarian cancers subtypes, our goal was to further study the association between BAF250a expression in cases of AE with and without an associated cancer.MethodsThree separate databases were screened for suspected cases of AE. Based on a detailed review of the pathology reports, we selected cases likely to contain AE for slide review. After slide review, tissue blocks were recalled to perform IHC for BAF250a in the associated cancer, AE, or typical endometriosis when present.ResultsThere were 35 cases of endometriosis-associated cancer and 8 cases of AE not associated with cancer. Atypical endometriosis was found on pathology review in 23 endometriosis-associated cancer cases (66%). In the 35 cancer cases, BAF250a IHC showed loss of expression in 14 cases. Atypical endometriosis was present in 10 of these cases, 6 of which showed BAF250a loss (60%). BAF250a loss was not observed in the 8 cases of AE not associated with cancer or in the contiguous AE of 13 cases, whereby BAF250a expression was retained in the associated cancer.ConclusionsBAF250a loss in AE is consistently associated with the development of BAF250a-negative endometriosis-associated cancers and appears to be an early event in most of these cases. This research provides additional evidence that in the absence of cancer, BAF250a expression should be evaluated as a biomarker of cancer risk in patients diagnosed with AE.

scholarly journals Evaluation of PTEN and Ki67 Expression in Typical and Atypical Endometriosis and Endometriosis Associated Ovarian Cancer

2020 ◽  
Vol 21 (11) ◽  
Author(s):  
Mojgan Akbarzadeh-Jahromi ◽  
Zahra Zare ◽  
Fatemeh Sari Aslani ◽  
Simin Torabinezhad
Keyword(s):  
Ovarian Cancer ◽  
Precancerous Lesion ◽  
Early Event ◽  
P Value ◽  
Ovarian Endometriosis ◽  
Ki 67 ◽  
Pten Loss ◽  
Epithelial Component ◽  
Increased Risk ◽  
Atypical Endometriosis

Background: Several studies reported that endometriosis is associated with an increased risk of ovarian cancer. Atypical endometriosis is common in patients with endometriosis-associated ovarian, which might be considered as a precancerous lesion. Objectives: This study aimed to assess ki67 and PTEN expression in endometriosis associated ovarian cancer (EAOC), atypical endometriosis, and typical endometriosis. Methods: In this study, all H & E slides of 260 ovarian endometriosis cases were reviewed. And 25 cases were diagnosed with atypical endometriosis. Forty-one typical endometrioses and 24 ovarian cancers with endometriosis were included. We assessed PTEN and Ki67 immunoexpression in epithelial and stromal cells. Results: The prevalence of atypical endometriosis was about 9%. PTEN loss was found in 12 (out of 24 or 50%) of EAOC, 2 (out of 25; 8%) of atypical endometriosis, and none of the typical endometriosis. In all 12 PTEN loss cases, the PTEN loss pattern in endometriosis adjacent to ovarian cancer was similar to that of ovarian cancer. A total of 7.3% of typical endometriosis and 8% atypical endometriosis and 33.3% of EAOC had Ki67 staining in more than 50% of the epithelial component. Both typical and atypical endometriosis showed similar PTEN loss and Ki 67 staining (in more than 50% of the epithelial component) (P value > 0.05), and both of them were different from EAOC (P value < 0.05). Conclusions: The PTEN loss pattern in endometriosis adjacent to ovarian cancer was similar to that of ovarian cancer. The result indicated that PTEN loss could be an early event in the tumor development pathway from endometriosis to ovarian cancer.

Functional profiling of clear cell ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5035-5035
Author(s):  
Rowan Miller ◽  
Rachel Brough ◽  
Ilirjana Bajrami ◽  
Stanley B. Kaye ◽  
Christopher J. Lord ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Throughput Screening ◽  
Clear Cell ◽  
Integral Functional ◽  
Therapeutic Targets ◽  
Molecular Profiling ◽  
Loss Of Function ◽  
Ovarian Carcinomas ◽  
Ovarian Cancers ◽  
Platinum Based Chemotherapy

5035 Background: Clear cell ovarian cancer represents up to 15% of epithelial ovarian cancers. In comparison to other subtypes, clear cell ovarian carcinomas have a poorer prognosis and are relatively resistant to standard platinum based chemotherapy. Recently, loss of function mutations in the tumour suppressor gene ARID1A were identified in up to 50% of ovarian clear cell carcinomas. We have adopted an integral functional and molecular profiling approach as a route to identify new genetic dependencies and therapeutic targets for this disease. Methods: Clear cell ovarian cancer cell lines were functionally profiled using high throughput screening with chemical and siRNA libraries. This has been integrated with molecular profiling data generated from exome and transcriptome sequencing to aid the discovery of novel targets. Results: Using functional screens we have now identified critical gene dependencies and potential therapeutics in a series of clear cell ovarian cancer models. The comparison of functional viability profiles for models characterized by ARID1A loss of function mutations is now enabling an analysis of synthetic lethal effects that could be used to target clear cell ovarian cancers carrying these mutations. Conclusions: The work undertaken so far provides the framework for the discovery of therapeutic targets for clear cell ovarian cancer using an integrated approach. Revalidation of these preliminary results is now underway to characterize new genetic dependencies for this disease.

scholarly journals Ovarian Cancer: Molecular Classification and Targeted Therapy

2021 ◽  
Author(s):  
Febina Ravindran ◽  
Bibha Choudhary
Keyword(s):  
Ovarian Cancer ◽  
Gynecological Cancer ◽  
Molecular Classification ◽  
High Recurrence Rate ◽  
Specific Gene ◽  
Cancer Subtypes ◽  
Ovarian Cancers ◽  
Precision Therapy ◽  
Advanced Stages ◽  
Druggable Targets

Ovarian cancer is the deadliest gynecological cancer among women with an overall 5-year survival rate below 50% due to its asymptomatic nature, diagnosis at advanced stages, and a high recurrence rate after standard therapy in 70% of cases. Ovarian cancers are heterogenous cancers where each subtype possesses a varied morphology and biologic behavior. Accumulating evidence has identified each of these subtypes characterized with specific pathways activated in each along with specific gene alterations. For example, high-grade serous ovarian cancer is characterized by universal TP53 mutation, mucinous ovarian cancer with KRAS mutation and clear cell or endometrioid ovarian cancers with ARID1A mutations. With the current focus of molecular-targeted therapies for cancer, such druggable markers serve as excellent targets for precision therapy and combination therapy. This chapter, provides an overview of the critical molecular pathways activated in the ovarian cancer subtypes with its druggable targets studied in ovarian cancer. We also highlight the implications of miRNAs in chemoresistance and sensitivity in the regulation of ovarian cancer.

scholarly journals Arginine depletion through ADI-PEG20 to treat argininosuccinate synthase deficient ovarian cancer, including small cell carcinoma of the ovary, hypercalcemic type

2019 ◽  
Author(s):  
Jennifer X. Ji ◽  
Dawn R. Cochrane ◽  
Basile Tessier-Cloutier ◽  
Shary Chen ◽  
Germain Ho ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Carcinoma ◽  
Small Cell Carcinoma ◽  
Small Cell ◽  
Mouse Xenograft ◽  
Cancer Subtypes ◽  
Ovarian Cancers ◽  
Carcinoma Of The Ovary

AbstractPurposeMany rare ovarian cancer subtypes such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) have poor prognosis due to their aggressive nature and resistance to standard platinum and taxane based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes.Experimental DesignWe compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype high grade serous ovarian cancer (HGSC) to identify potential therapeutic targets. Immunohistochemistry of tissue microarrays were used as validation of ASS1 deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient derived xenograft mouse models representing SCCOHT.ResultsGlobal proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared to HGSC. Low ASS1 levels were validated through IHC in a large patient cohort. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 2/15 cases, and expressed in less than 5% of the tumor cells in 8/15 cases. ASS1 deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient derived mouse xenograft model of SCCOHT, once a week treatment of ADI-PEG20 (30mg/kg and 15mg/kg) inhibited tumor growth in vivo.ConclusionsPreclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers including SCCOHT.Translational relevanceMany rare ovarian cancers lack effective management strategies and are resistant to the standard platinum- and taxane-based chemotherapy. Thus, for a rare ovarian cancer subtype like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) - an aggressive malignancy affecting young women in their twenties, effective targeted therapeutics are urgently needed. We used global proteomics to identify a deficiency in arginosuccinate synthase (ASS1) as a common feature among some rare ovarian cancer subtypes. Using in-vitro and in-vivo models, we demonstrated that the arginine-depriving investigational agent ADI-PEG20 effectively inhibited cell growth in ASS1 deficient ovarian cancers including SCCOHT, establishing it as a potential therapeutic agent for rare ovarian cancer subtypes deficient in ASS1. Further clinical investigation is warranted.

scholarly journals Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium

2016 ◽  
Vol 34 (24) ◽  
pp. 2888-2898 ◽  
Author(s):  
Nicolas Wentzensen ◽  
Elizabeth M. Poole ◽  
Britton Trabert ◽  
Emily White ◽  
Alan A. Arslan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ovarian Cancer ◽  
Clear Cell ◽  
Low Grade ◽  
Significant Heterogeneity ◽  
Ratio Test ◽  
Ovarian Cancer Risk ◽  
Histologic Subtype ◽  
Cancer Subtypes ◽  
Increased Risk

Purpose An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). Patients and Methods Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. Results Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. Conclusion The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.

scholarly journals Endometriosis-assEndometriosis-associated ovarian tumors: morphological and immunohistochemical features

2019 ◽  
Vol 9 (2) ◽  
pp. 12-19
Author(s):  
N. N. Bayramova ◽  
A. E. Protasova ◽  
G. A. Raskin ◽  
M. S. Sobivchak ◽  
M. I. Yarmolinskaya
Keyword(s):  
Ovarian Cancer ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Ovarian Tumors ◽  
Ki 67 ◽  
Immunohistochemical Markers ◽  
Endometrioid Ovarian Cancer ◽  
Carcinoma Of The Ovary ◽  
Atypical Endometriosis

Background. In 2016, the World Health Organization published an updated version of the Histological Classification for ovarian tumors presenting a new category of endometriosis-associated tumors. The predictors of malignant transformation of endometriosis have not been clearly defined so far.Purpose. The search for histological and immunohistochemical markers of endometriosis-associated malignancy.Materials and methods. 28 female patients with endometrioid ovarian cancer and 11 patients with clear cell ovarian carcinoma were enrolled. Histological and immunohistochemical studies were carried out using conventional techniques. Immunohistochemistry was applied to determine the hormone receptor status: expression of steroid hormone receptors, BAF250a (ARID1A), PTEN, P-catenin, MSH6, PMS2, р-53, WT-1, proliferative index (Ki-67). Microsatellite instability (MSI) testing was conducted according to the standard protocol.Results. In all cases of ovarian cancer, histological examination showed one of the endometriosis features. Atypical endometriosis was found in 39 % (11 / 28) of endometrioid tumors and in 9% (1/ 11) of clear cell carcinomas. Endometrioid ovarian cancer was found to be ER (74±7,8%) — and PR (67±5,4%) — positive; Ki-67 index was 68,2±3,7 %; loss of BAF250a (ARID1A) expression was observed in 14% (4/ 28), loss of PTEN expression in 29 % (8 / 28), nuclear expression of P-catenin in 32% (9/28) of cases. Loss of MMR expression was detected in 7% (2/28) of cases. MSI was found in one case only, which was also associated with loss of expression of BAF250a (ARID1A) and MSH6. Clear cell carcinoma of the ovary showed histological criteria for endometriosis; however, there were no changes immunohistochemical markers expression that were typical for endometriosis-associated malignancies. It could be due to a small number of patients in the group so further research is needed.Conclusion. Atypical endometriosis may be a morphological precursor of endometrioid and clear cell carcinoma of the ovary. Comprehensive assessment of a marker panel consisting of BAF250a (ARID1A), P-catenin, PTEN, p53, Ki-67 index, PMS2 and MSH6 will allow improving the diagnosis of atypical endometriosis and endometriosis-associated ovarian cancer.

scholarly journals Somatic Mutations in BRCA1 and BRCA2 Could Expand the Number of Patients That Benefit From Poly (ADP Ribose) Polymerase Inhibitors in Ovarian Cancer

2010 ◽  
Vol 28 (22) ◽  
pp. 3570-3576 ◽  
Author(s):  
Bryan T.J. Hennessy ◽  
Kirsten M. Timms ◽  
Mark S. Carey ◽  
Alexander Gutin ◽  
Larissa A. Meyer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Quantitative Polymerase Chain Reaction ◽  
Positive Association ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Ovarian Cancers ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Parp1 Inhibitors ◽  
Expression Loss

Purpose The prevalence of BRCA½ mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA½ changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs. Patients and Methods In 235 unselected ovarian cancers, BRCA½ was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA½ transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA½ mutations, germline DNA was sequenced. Results Forty-four mutations (19%) in BRCA1 (n = 31)/BRCA2 (n = 13) were detected, including one homozygous BRCA1 intragenic deletion. BRCA½ mutations were particularly common (23%) in high-grade serous cancers. In 28 patients with available germline DNA, nine (42.9%) of 21 and two (28.6%) of seven BRCA1 and BRCA2 mutations were demonstrated to be somatic, respectively. Five mutations not previously identified in germline DNA were more commonly somatic than germline (four of 11 v one of 17; P = .062). There was a positive association between BRCA1 and TP53 mutations (P = .012). BRCA½ mutations were associated with improved progression-free survival (PFS) after platinum-based chemotherapy in univariate (P = .032; hazard ratio [HR] = 0.65; 95% CI, 0.43 to 0.98) and multivariate (P = .019) analyses. BRCA½ deficiency, defined as BRCA½ mutations or expression loss (in 24 [13.3%] BRCA½–wild-type cancers), was present in 67 ovarian cancers (30%) and was also significantly associated with PFS in univariate (P = .026; HR = 0.67; 95% CI, 0.47 to 0.96) and multivariate (P = .008) analyses. Conclusion BRCA½ somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.

Rare Epithelial Tumors Arising in or near the Ovary: A Review of the Risk Factors, Presentation, and Future Treatment Direction for Ovarian Clear Cell and Mucinous Carcinoma

2013 ◽  
pp. e200-e204
Author(s):  
Angela Jain ◽  
Michael V. Seiden
Keyword(s):  
Clear Cell ◽  
Tumor Biology ◽  
Total Abdominal Hysterectomy ◽  
Mucinous Carcinoma ◽  
Treatment Recommendation ◽  
Early Event ◽  
Advanced Stage ◽  
Bilateral Oophorectomy ◽  
Ovarian Cancers ◽  
Stage Disease

Currently all advanced-stage epithelial ovarian cancers are treated with a total abdominal hysterectomy, bilateral oophorectomy, and complete tumor debulking surgery, followed by carboplatin and paclitaxel. This treatment recommendation is based on clinical trials that are mostly populated with women with high-grade serous carcinomas. Patients with mucinous or clear cell carcinomas of the ovary tend to present with earlier-stage disease, and may not require adjuvant chemotherapy; those with advanced-stage disease tend to have carboplatin-resistant disease. Patients with mucinous ovarian carcinoma have presentations and tumor biology that are similar to colorectal carcinomas and may benefit from colorectal regimens containing fluorouracil (FU) and oxaliplatin. Their tumors may also be KRAS wild-type or have HER2 amplification, and could benefit from drugs like cetuximab or trastuzumab. Patients with clear cell carcinoma of the ovary often harbor AIRD1a mutations, an early event in oncogenesis that is not a currently drugable target. Anecdotal cases and our biologic understanding of these malignancies suggest they might be preferentially sensitive to antiangiogenesis inhibitors. Focused international trials will be needed in both of these rare epithelial ovarian cancers to better define optimal treatment regimens.

scholarly journals The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Giovanni Grandi ◽  
Angela Toss ◽  
Laura Cortesi ◽  
Laura Botticelli ◽  
Annibale Volpe ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Suppressor Genes ◽  
Clear Cell ◽  
Low Grade ◽  
Retrograde Menstruation ◽  
Molecular Alterations ◽  
Ovarian Cancers ◽  
Increased Risk ◽  
Reproductive Life ◽  
Endometrioid Ovarian Cancer

Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life.

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