bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B14: IGF axis proteins are the main carcinogens in ovulatory follicular fluid: Evidences from a mammary fat pad tumorigenesis model
Authors: Huang Hsuan-Shun , Chu Sung-Chao , Chu Tang-Yuan 
Published: August 2018

Abstract
Ovarian high-grade serous carcinoma (HGSC) is the most devastating gynecologic cancer with elusive etiology and poor prognosis. Previous studies have disclosed that TP53 mutation is the universal and earliest genetic hit in its origin in the fallopian tube fimbriae. We and others have reported that ROS in ovulatory follicular fluid (FF) is the main mutagen that induces DNA double-strand breaks in fimbrial epithelial cells. However, ROS alone could not explain the transformation activity of FF found by our early study. In parallel studies (abstract by Chu TY et al.), we disclosed the presence of inactive IGF axis proteins in FF, including IGFBP-bonded IGFs and the GAG-free PAPP-A cleaving enzyme. Upon docking to the cell membrane at GAG sites, PAPP-A cleaves IGFBP, frees IGF to bind with IGF-1R, activates the downstream PI3K/Akt/mTOR signaling pathway, and results in the full transformation of the p53/Rb-null immortalized fimbrial epithelial cells. In this study, we established a tumorigenesis induction model in Trp53-/- mice to study the carcinogenic activity of FF. Upon repeated injection of ROS-high FF into the mammary fat pad of Trp53-/- mice, 10 of the 18 (56%) mice grew tumor around the injection site within 8 weeks. The histology showed small and mature B cell non-Hodgkin lymphoma. In contrast, no tumor growth was noted by 16 weeks when FF was injected subcutaneously or when mice were castrated. When IGF2 was depleted from the FF by monoclonal antibody, there was no tumor growth 8 weeks after the same repeated fat pad injections. By contrast, repeated injection of 100ng/ml IGF2 resulted in tumorigenesis in 33% (2/6) of the mice. The study provides in vivo evidence showing that other than ROS, IGF axis proteins are the main carcinogen in ovulatory follicular fluid.
Citation Format: Hsuan-Shun Huang, Sung-Chao Chu, Tang-Yuan Chu. IGF axis proteins are the main carcinogens in ovulatory follicular fluid: Evidences from a mammary fat pad tumorigenesis model. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B14.
Abstract B39: The origins of endometriosis-associated cancers
Authors: Cochrane Dawn , Tessier-Cloutier Basile , Lawrence Katherine , Nazeran Tayyebeh , Karnezis Anthony , Salamanca Clara , Lee Timothy , Cheng Angela , McAlpine Jessica , Hoang Lien , Gilks Blake , Huntsman David 
Published: August 2018

Abstract
Both clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are associated with ovarian endometriotic cysts, which is believed to be the precursor lesion of these cancers. Women with endometriotic cysts have up to a 3-fold increased risk of developing CCOC and ENOC. It is perplexing that these two clinically distinct histotypes of ovarian cancer arise from the same precursor lesion. We have performed whole-genome sequencing of ovarian cancer histotypes and found that while some genomic features are more common to one histotype than the other, there is not a single feature that is unique to either histotype. Lacking genomic evidence that could explain the differences between these histotypes, we hypothesized that these cancers arise from distinct cells of origin within endometrial tissue, and the cellular context accounts for their differences. We performed global proteomic analysis of ovarian cancer histotypes and identified CTH as a marker for CCOC. Upon examination of normal Müllerian tissues, we found that CTH is highly expressed in the ciliated cells of endometrium (both ectopic endometrium and endometriosis) and of the fallopian tube, with very little expression in the secretory cells of these tissues. We also find that other ciliated cell markers are expressed in CCOC, whereas endometrial secretory cell markers are expressed in ENOC. We propose a new model of CCOC and ENOC histogenesis wherein ENOC is derived from cells of secretory cell lineage whereas CCOC is derived from, or shares similarities to, cells of ciliated cell lineage. There remain, however, many unanswered questions. For example, while CCOC and ENOC occur at roughly equal prevalence, ciliated cells of the endometrium are rare compared to secretory cells. Cells in the endometriotic cyst are exposed to factors such as inflammation and reactive oxygen species, which could influence differentiation of endometrial progenitor cells into the secretory or ciliated cell lineage. To test factors that promote ciliated cell differentiation in normal endometrium, we treated organoid cultures of normal endometrium with IL-6 and Notch pathway modulators. We propose that ovarian cancer histotypes arise from different cells of origin and that the biology of the normal cells will be partly responsible for determining the phenotype of the cancers.
Citation Format: Dawn Cochrane, Basile Tessier-Cloutier, Katherine Lawrence, Tayyebeh Nazeran, Anthony Karnezis, Clara Salamanca, Timothy Lee, Angela Cheng, Jessica McAlpine, Lien Hoang, Blake Gilks, David Huntsman. The origins of endometriosis-associated cancers. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B39.
Abstract B44: Early loss of monoubiquitylation of H2B alters key metabolic and immune signaling pathways promoting the progression of high-grade serous ovarian cancer
Authors: Hooda Jagmohan , Novak Marian , MacDuffie Emily , Song Melissa , Lester Jenny , Parkash Vinita , Mills Gordon B. , Karlan Beth Y. , Oren Moshe , Drapkin Ronny 
Published: August 2018

Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most common form of ovarian cancer, accounting for over 70% of all cases. HGSOC is frequently complicated by the inevitable development of therapeutic resistance, and thus remains an incurable disease. Recent insights supporting the fallopian tube epithelium (FTE) as a point of origin for HGSOC and the serous tubal intraepithelial carcinoma (STIC) as the precursor lesion for a majority of HGSOCs provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Understanding these key molecular processes is essential to inform the development of next-generation therapies. In this study we investigated the role of the ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis. H2Bub1, catalyzed largely by RNF20, is an epigenetic mark with tumor-suppressor properties. The loss of RNF20/H2Bub1 has been linked with cancer progression. We used immunohistochemistry to characterize the expression of H2Bub1 in HGSOC and FTE precursors. We found that H2Bub1 is lost or downregulated in a large proportion of STICs and HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in serous tumorigenesis. Consistent with our findings, analysis of TCGA data shows that the majority of HGSOCs exhibit heterozygous loss of RNF20. Functionally, we demonstrated that shRNA-mediated knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to increase cell migration and clonogenic growth of immortalized FTE cells. To understand the mechanisms underlying these effects, we performed RNA-seq and proteomics profiling (RPPA) in RNF20 knockdown cells. Major changes were observed in a number of structural, metabolic (e.g., glutamine pathway), and cytokines and inflammatory signaling pathways, providing early mechanistic insights for the observed oncogenic phenotypes. In summary, our study identifies that loss of H2Bub1 is an early epigenetic event in HGSOC that rewires glutamine metabolism and certain inflammatory pathways, which may represent unique therapeutic opportunities.
Citation Format: Jagmohan Hooda, Marian Novak, Emily MacDuffie, Melissa Song, Jenny Lester, Vinita Parkash, Gordon B. Mills, Beth Y. Karlan, Moshe Oren, Ronny Drapkin. Early loss of monoubiquitylation of H2B alters key metabolic and immune signaling pathways promoting the progression of high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B44.
Abstract B46: DICER1 and FOXL2 mutations correlate with clinicopathologic features of ovarian Sertoli-Leydig cell tumors
Authors: Karnezis Anthony N. , Wang Yemin , Magrill Jamie , Keul Jacqueline , Kommoss Stefan , Tessier-Cloutier Basile , Proctor Lily , Schmidt Dietmar , Gilks C Blake , Huntsman David G. , Kommoss Friedrich 
Published: August 2018

Abstract
Sertoli-Leydig cell tumors are rare mixed ovarian sex cord-stromal neoplasms consisting of a mixture of Sertoli cells, Leydig cells, and occasionally heterologous elements or retiform differentiation. The only known recurrent genetic abnormality is mutations in DICER1, with rare mutations reported in FOXL2. We set out to determine the DICER1 and FOXL2 mutation status in a series of 51 SLCTs with the goal of establishing a molecular classifier using mutation status and clinicopathologic features. Five tumors were well differentiated, 39 moderately differentiated, and 7 poorly differentiated. Nine tumors had heterologous elements (8 epithelial, one mesenchymal), and four showed retiform differentiation; all of these were moderately differentiated. DICER1 mutations were identified in 16/45 of successfully genotyped tumors (36%, 15 moderately differentiated, 1 poorly differentiated), including 7 with heterologous elements and 3 of 4 with retiform differentiation. FOXL2 c.402C&gt;G mutation was identified in 10/51 tumors (20%, 8 moderately differentiated, 2 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the entire cohort was 44 years (range 15-90). Patients with DICER1 mutations were younger (median 23.5 years, range 15-62) than patients with neither DICER1 nor FOXL2 mutation (median 41.5 years, range 16-74). Tumors with FOXL2 mutation occurred exclusively in postmenopausal patients (median 78 years, range 54-90), whereas 11/13 tumors with either heterologous elements (median 26 years, range 16-62) or retiform differentiation (median 38 years, range 18-57) occurred in premenopausal patients. Our data suggest the existence of at least three molecular subtypes of SLCT: DICER1 mutant (younger, moderately/poorly differentiated, including heterologous elements or retiform differentiation), FOXL2 mutant (postmenopausal, moderately/poorly differentiated, no heterologous elements or retiform differentiation), and DICER1/FOXL2 wild-type (no specific age, no heterologous elements, including all well-differentiated tumors). These findings suggest that well-differentiated and moderately/poorly differentiated SLCTs may be different histomolecular entities with different etiologies.
Citation Format: Anthony N. Karnezis, Yemin Wang, Jamie Magrill, Jacqueline Keul, Stefan Kommoss, Basile Tessier-Cloutier, Lily Proctor, Dietmar Schmidt, C Blake Gilks, David G. Huntsman, Friedrich Kommoss. DICER1 and FOXL2 mutations correlate with clinicopathologic features of ovarian Sertoli-Leydig cell tumors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B46.
Abstract B47: Rgnef (p190RhoGEF/Arhgef28) loss impairs ovarian tumor metastatic growth
Authors: Kleinschmidt Elizabeth G. , Tancioni Isabelle , Taylor Kristin , Osterman-Diaz Carlos , Miller Nichol L. G. , Jiang Shulin , Schlaepfer David D. 
Published: August 2018

Abstract
Increased activation of FAK and Rho GTPase regulatory pathways is associated with shorter survival in patients with high-grade serous ovarian carcinoma (HGSOC). However, the key mediators of these signaling events in HGSOC remain unknown. We have previously shown that the Rho guanine nucleotide exchange factor Rgnef (also named p190RhoGEF or Arhgef28) activates FAK as well as RhoA GTPase in mouse fibroblasts. Here we find that Rgnef protein expression is elevated in Stage 3-4 HGSOC and that Rgnef knockout prevents ovarian tumor spheroid growth in vitro and in vivo. We isolated ascites-associated murine ID8 cells to generate a more aggressive cell line, termed ID8-IP. ID8-IP cells exhibit higher Rgnef and FAK expression than parental ID8 cells. CRISPR/Cas9-induced knockout of Rgnef in ID8-IP cells does not alter 2D growth as compared to Rgnef-KO cells re-expressing GFP-Rgnef. However, Rgnef loss significantly decreased growth as spheroids in a 3D Matrigel-on-Top assay. At five weeks following intraperitoneal injection into syngeneic C57Bl/6 mice, ID8-IP Rgnef-KO cells form significantly fewer ascites-associated cells, as well as fewer metastatic lesions on the peritoneal wall. Notably, ID8-IP Rgnef-KO cells display lower FAK and ERK1/2 phosphorylation. These studies demonstrate that Rgnef loss impedes metastatic growth in the peritoneal cavity, and suggest that an integrin-mediated Rgnef-FAK linkage facilitates ovarian tumor metastasis.
Citation Format: Elizabeth G. Kleinschmidt, Isabelle Tancioni, Kristin Taylor, Carlos Osterman-Diaz, Nichol L. G. Miller, Shulin Jiang, David D. Schlaepfer. Rgnef (p190RhoGEF/Arhgef28) loss impairs ovarian tumor metastatic growth. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B47.
Abstract B68: Adnexal tumors associated with endometriosis: Experience from an academic institution
Authors: Desouki Mohamed Mokhtar 
Published: August 2018

Abstract
Background: Endometriosis affect pelvic organs in ~10% of cases. The question of endometriosis being a precancerous lesion versus an incidental association with adnexal (fallopian tubes and ovaries) tumors is a point of debate. This study aimed to determine the frequency of adnexal tumors in cases with histologically proven endometriosis of adnexal structures at our institution.
Methods: A retrospective chart review of patients diagnosed with adnexal endometriosis from 2013-2017 was performed. Patients’ age, demographic data, and associated ipsilateral benign or malignant adnexal tumors were obtained from the pathology notes.
Results: 151 cases with a histologically verified endometriosis of fallopian tubes and/or ovaries were retrieved. The average age of the patients was 42 years (range of 22-78 years). The race/ethnic groups of the patients were white, black, and others in 120 (79%), 17 (11%) and 14 (9%), respectively. Associated malignant tumors were identified in 8 (5.3%) cases while 10 (6.6%) cases were found to have benign neoplasms in the ipsilateral site of endometriosis. The malignant tumors were endometrioid adenocarcinoma (n=4), high-grade serous carcinoma (n=3), and clear cell carcinoma (n=1). The benign neoplasms were serous cystadenoma/ cystadenofibroma (n=7) and seromucinous tumors (n=3).
Conclusions: The incidence of malignant neoplasms, especially endometrioid and high-grade serous carcinoma, is relatively high in cases with histologically verified endometriosis in our experience. Among benign tumors, serous cystadenoma and seromucinous neoplasms appear to be frequently associated with endometriosis. More studies are needed to further highlight the significance of adnexal endometriosis in causation of malignant and benign adnexal tumors.
Citation Format: Mohamed Mokhtar Desouki. Adnexal tumors associated with endometriosis: Experience from an academic institution. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B68.
Abstract B74: Identification of prognostic molecular subtypes of ovarian serous cystadenocarcinoma by isoform-level gene expression analysis
Authors: Shilpi Arunima , Seagle Brandon L. , Kandpal Manoj , Shahabi Shohreh , Davuluri Ramana V. 
Published: August 2018

Abstract
Characterization of molecular aberrations in ovarian serous cystadenocarcinoma (OVSC) is highly crucial for developing precision medicine approaches. While gene-level analysis of gene expression profiles of The Cancer Genome Atlas (TCGA) OVSC samples revealed four molecular subgroups (differentiated, proliferative, mesenchymal, and immunoreactive), the association of the derived subtypes with the clinical and pathologic features, such as stage, cytoreduction, and chemotherapy, is not statistically significant. Considering the fact that the majority of human genes produce multiple transcript-variants that could be involved in different functional pathways, we reanalyzed the TCGA exon-array expression profiles at the transcript variant or isoform level by following the novel informatics methodology we developed and successfully applied for glioblastoma (Pal et al., Nucleic Acids Res 2014). Non-negative matrix factorization (NMF) clustering of TCGA ovarian serous adenocarcinoma samples, based on isoform-level gene-expression profiles, recaptured the four known molecular subgroups but switched the subtype for 26% of the samples, resulting in significant (p=0.009) survival differences among the refined subgroups. The survival analysis was further extended to multivariate Cox proportional hazard model considering the different subgroups, and the clinical parameters as the predictor variables. Patients classified under mesenchymal group (HR = 1.44; 95% CI, 0.99-2.08; P &lt; 0.05) and in stage III (HR = 2.39, 95%of CI, 1.25-4.56, P &lt; 0.05), IV (HR= 3.16; 95% of CI, 1.58-6.32, P &lt; 0.05) were identified to be at high risk or decreased survival, while those receiving intraperitoneal (IP) chemotherapy (HR, 0.63; 95% of CI, 0.38-1.03, P &lt; 0.1) were associated with longer survival. We are in the process of translating the isoform-level gene signature into clinically adaptable molecular subtyping assay and validating on an independent patient cohort, with potential implications for developing robust diagnostic assays for OVSC patient stratification.
Citation Format: Arunima Shilpi, Brandon L. Seagle, Manoj Kandpal, Shohreh Shahabi, Ramana V. Davuluri. Identification of prognostic molecular subtypes of ovarian serous cystadenocarcinoma by isoform-level gene expression analysis. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B74.
Abstract IA01: PARP inhibitors as single agents and in combinations for ovarian cancer: What lies ahead?
Authors: Matulonis Ursula A. 
Published: August 2018

Abstract
Poly (ADP ribose) polymerase (PARP) inhibitors are an exciting and promising new class of anticancer drugs. Initial clinical trials of PARP inhibitors began over a decade ago following the discovery that PARP inhibitors in vitro had heightened anticancer activity in BRCA mutated cancer cells compared to BRCA wild-type cells. PARP inhibitor clinical development has taken several strategies, including single-agent and combination testing. Single-agent PARP inhibitors have been used as either primary treatment of recurrent ovarian cancer or as maintenance treatment following anticancer response after platinum-based chemotherapy. Three PARP inhibitors are now FDA approved for recurrent ovarian cancer, all as single agents: 1) olaparib for patients with recurrent germline BRCA mutated ovarian cancer who have received 3 or more prior lines of chemotherapy and also as maintenance therapy post-platinum therapy for patients with platinum sensitive recurrence who are in response to platinum-based chemotherapy and regardless of BRCA or tumor HR status; 2) rucaparib for patients with BRCA mutated ovarian cancer (either deleterious tumor or germline mutation) who have received at least 2 prior lines of chemotherapy; and 3) niraparib for platinum-sensitive recurrent ovarian cancer patients as maintenance therapy who are in response to platinum-based chemotherapy and regardless of BRCA or tumor HR status. Because of the myelosuppression observed with PARP inhibitors, combining these agents with chemotherapy has been difficult and has required lowering the doses of either the PARP inhibitor and/or the chemotherapy agents and often abbreviating the treatment schedule; several negative phase III studies have been reported. Combining PARP inhibitors with biologic agents is another strategy currently being tested in clinical trials and one that avoids overlapping toxicities. The combination of the PARP inhibitor olaparib and the antivascular endothelial growth factor receptor agent cediranib has shown promising phase II results against olaparib alone, especially in BRCA wild-type ovarian cancer. These results have led to phase III studies comparing the olaparib and cediranib combination to standard therapies (NCT02502266 and NCT02446600). Other studies are under way testing PARP inhibitors with other biologic agents such as immunotherapy agents and other targeted agents such as ATR inhibitors, PI3 kinase inhibitors, and heat shock protein 90 inhibitors.
Citation Format: Ursula A. Matulonis. PARP inhibitors as single agents and in combinations for ovarian cancer: What lies ahead? [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA01.