bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA15: Rarer, yet both interesting and relevant: Other ovarian cancers.
Authors: Huntsman David G. 
Published: May 2016

Abstract
Although high grade serous ovarian carcinoma is justifiably the focus of most research and clinical attention, other histotypes represent significant clinical challenges. An overview of advances in our understanding of germ cell, sex cord-stromal and non-serous cancers will be presented. Specific attention will be placed on granulosa cell tumor and small cell hypercalcemic ovarian cancer where molecular features have both redefined those diseases and offered hope for more rational treatment plans.
Citation Format: David G. Huntsman. Rarer, yet both interesting and relevant: Other ovarian cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA15.
Abstract IA18: Thinking outside the box: New areas in prevention research.
Authors: Tworoger Shelley S. 
Published: May 2016

Abstract
Due to its high fatality, ovarian cancer is a key public health problem. Identifying high-risk women is particularly important, as bilateral salpingo-oophorectomy reduces risk by &gt;90%; However, because this surgery has other negative health consequences (e.g., increased risk of heart disease), it is indicated only for women with BRCA or other high-risk genetic variants. Unfortunately, current etiologic understanding of ovarian cancer and its risk factors does not have the predictive capacity needed to identify women who could benefit from prophylactic surgery. Thus the primary goal of prevention research is to identify new, potentially modifiable risk factors for ovarian cancer that have the capability to both improve risk prediction and create new opportunities for other prevention modalities. A number of challenges, including tumor heterogeneity, require “out-of-the-box” approaches to conducting prevention research. In this talk, I will discuss several examples of opportunities to advance prevention research including novel approaches to characterizing ovarian tumors in epidemiologic studies, using basic research to motivate the evaluation of new potential risk factors, and considering etiologically susceptible windows of exposure. Finally, I will discuss existing consortial resources within the ovarian cancer research community that are open to collaboration.
Citation Format: Shelley S. Tworoger. Thinking outside the box: New areas in prevention research. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA18.
Abstract IA24: Developing and deploying experimental models systems towards novel drug discovery in ovarian cancer.
Authors: Drapkin Ronny , Budina Anna , Feng Yi , Doberstein Kai 
Published: May 2016

Abstract
Ovarian cancer carries significant mortality in the absence of effective methods for prevention and screening. Preventive salpingo-oophorectomy is currently the only method known to reduce the risk of ovarian cancer-related death. Histopathological analyses of these surgical specimens indicate that a high proportion of ovarian cancers in women at high risk and in the general population arise from the fallopian tube. This paradigm shift in our understanding of the cell of origin for the most common subtype of ovarian cancer, high-grade serous carcinoma, has sparked a major effort within the research community to develop new and robust model systems to study the fallopian tube epithelium, it susceptibility to neoplastic transformation, and opportunities for therapeutic intervention.
These models include primary cell line cultures, fallopian tube-derived lines, epithelial-stromal co-cultures, genetically-engineered mouse models, and patient-derived tumor xenografts or ‘avatars’. There has also been a re-evaluation of the fidelity of established ovarian cancer cell lines and the need to develop new lines that represent the human disease. Critical to this effort is the need to go beyond genomics and critically evaluate the functional utility of new cell lines.
The deploying of these new models is already have a profound effect on our ability to identify unique susceptibilities in ovarian cancer through genetic screens, chemical screens, and targeted approaches. In addition, the search for novel biomarkers that can play a role in early detection or prognostication is being re-defined by looking at the fallopian tube fimbria as the source.
Citation Format: Ronny Drapkin, Anna Budina, Yi Feng, Kai Doberstein. Developing and deploying experimental models systems towards novel drug discovery in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA24.
Abstract IA26: Role of ARID1A in SWI/SNF chromatin remodeling and ovarian cancer.
Authors: Chandler Ronald L. , Raab Jesse , Magnuson Terry 
Published: May 2016

Abstract
ARID1A has emerged as the most frequently mutated chromatin remodeling protein in cancer and as a major tumor suppressor in endometriosis-associated cancers arising from the coelomic epithelium of the female reproductive tract. We have developed and characterized Arid1a conditional (floxed) and hypomorphic (valine-to-glycine substitution or V1068G) mutant mouse alleles. Mutant ARID1AV1068G is stably expressed and capable of assembling into a SWI/SNF complex with core catalytic properties, but nucleosome binding and promoter occupancy by ARID1A-containing SWI/SNF complexes (BAF-A) are reduced. Lowly penetrant hyperplastic outgrowths are observed within the oviducts of aged, hypomorphic Arid1aV1068G/+ females, but no tumors have been detected. Conversely, conditional inactivation of ARID1A in the ovarian surface epithelium (OSE) via intrabursal Adenovirus-CRE injection is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, mouse ovarian tumor cells carrying the ARID1A-PIK3CA mutational pattern are genomically stable, chemoresistant and dependent on cell autonomous Interleukin 6 (IL-6) signaling pathway for continued growth and survival. We have further shown that concurrent ARID1A loss and PIK3CA activation leads to an epithelial-to-mesenchymal transformation phenotype in isolated OSE cells. Our data highlight potential gene dose-dependent differences in ARID1A tumor suppressor activity in coelomic epithelial cell derivatives and suggest that many key features of ovarian tumorigenesis are conferred by the ARID1A-PIK3CA mutational pattern. Hence, our efforts to parse the tumor suppressor roles of ARID1A-containing SWI/SNF complexes in endometriosis-associated gynecologic cancers should extend to the Müllerian-derived ductal epithelium and include activating phosphoinositide 3-kinase mutations.
Citation Format: Ronald L. Chandler, Jesse Raab, Terry Magnuson. Role of ARID1A in SWI/SNF chromatin remodeling and ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA26.
Abstract PR08: Evidence for extra-ovarian origin and peritoneal metastases that precede ovarian carcinomas in high-grade serous ovarian cancer.
Authors: Chien Jeremy , Shridhar Viji , Mariani Andrea 
Published: May 2016

Abstract
High-grade serous (HGS) ovarian cancer is the most lethal form of epithelial ovarian cancer because it represents the most common histologic subtype and usually present at an advanced stage. Due to its advanced stage presentation, HGS ovarian cancer has been described as arising de novo from undefined precursor lesions that progress rapidly to advanced disease. To gain insights into clonal heterogeneity and progression to distant metastases, we analyzed single nucleotide variations (SNVs) from nine regions of carcinomas from four patients with HGS ovarian cancer. Three primary sites, three metastases from omentum, and three metastases from bowel were collected from each patient and subjected to RNA sequencing and SNV analysis. Although a modest number (23.62%) of SNVs are shared within the same anatomic site, only limited number (1.26%) of SNVs are shared among all 9 sites, suggesting a high degree of intratumor heterogeneity in these patients. Truncal mutations, such as TP53 mutations, are shared among all sites and observed at high allele frequencies. In addition, mutations in genes associated with epigenetic modifiers, such as SETD2, CHD8, KDM5A, SMARCA1 and ARID5B are observed as truncal mutations in these patients. Phylogenetic tree reconstruction of tumors from various sites suggests a concurrent ovarian and peritoneal metastases in one patient and peritoneal metastases preceding the ovarian carcinomas in three other patients. Finally, subclone inference from multi-region sequencing indicates the presence of multiple subclones at each site in these patients. Dominant subclones, present at metastases, are often ancestral clones in the clonal hierarchy, further providing evidence that peritoneal spreading occurs early in the clonal expansion. Collectively, these results provide evidence for early peritoneal spreading that often precedes ovarian carcinomas in HGS ovarian cancer.
This abstract is also presented as Poster B44.
Citation Format: Jeremy Chien, Viji Shridhar, Andrea Mariani. Evidence for extra-ovarian origin and peritoneal metastases that precede ovarian carcinomas in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr PR08.
Abstract PR09: Ovarian cancer prevention: is it time for population screening for BRCA mutations?
Authors: Campbell Ian G. , Mitchell Gillian , Trainer Alison , James Paul , Thompson Ella 
Published: May 2016

Abstract
The traditional model of familial ovarian cancer practice involves ascertaining high-risk individuals based on family history. However, most individuals who carry a BRCA1 or BRCA2 mutation will not have a family history of ovarian or other cancer in a close relative. Moving germline testing from the familial cancer center to the population will result in many essentially unanticipated findings of great significance in regards to the risk of ovarian cancer in healthy relatives. To date there have been no large studies that have directly measured the frequency of BRCA1 and BRCA2 mutations in a cancer-free general population. As a first step toward population based BRCA1 or BRCA2 screening, we sequenced the entire coding region of these genes in 1,997 cancer-free Australian women recruited from the lifepool study (www.lifepool.org) which is a cohort of women attending the Australian population based mammographic screening program. Sequencing data were filtered for known pathogenic or novel loss of function mutations. Thirteen individuals were identified with pathogenic mutations in either BRCA1 (4 mutations) or BRCA2 (9 mutations), which is consistent with previous indirect estimates for Caucasian populations but to our knowledge this is the largest direct assessment of their prevalence.
Interestingly, the self-reported cancer family history of the majority of the 13 mutation positive women was unremarkable. All 13 women subsequently accepted an invitation to attend a Familial Cancer Centre and then proceeded to formal clinical genetic testing.
A population carrier frequency of 0.65% for mutations in BRCA1 and BRCA2, coupled with the rapidly declining costs of gene panel sequencing, suggests that population-based screening for these genes will be a highly cost effective way of reducing the incidence of ovarian (and breast) cancer through preventative strategies.
Citation Format: Ian G. Campbell, Gillian Mitchell, Alison Trainer, Paul James, Ella Thompson. Ovarian cancer prevention: is it time for population screening for BRCA mutations? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr PR09.
Abstract PR12: Mutant p53 drives early events in fallopian tube tumorigenesis through mesenchyme-associated autocrine production of matrix that supports survival and mesothelial intercalation.
Authors: Iwanicki Marcin P. , Chen Hsing-Yu , Zervantonakis Ioannis , Novak Marian , Muranen Taru , Ince Tan A. , Drapkin Ronny , Brugge Joan S. 
Published: May 2016

Abstract
High-grade serous ovarian cancer (HGS-OvCa) harbor p53 mutations and predominantly originates from the secretory epithelial cell compartment of the fallopian tube fimbriae. From this site, tumor cells detach, survive in the peritoneal cavity, and form cellular clusters that clear the mesothelium and expand to form peritoneal masses. To examine the contribution of mutant p53 to any of these phenotypic alterations associated with HGS-OvCA tumor progression, we developed live-cell microscopy assays that recapitulate these phenotypes and examined dynamic processes regulated by depletion of p53 or gain-of-function (GOF) mutations in p53 in cultured secretory fallopian tube epithelial cells. Expression of GOF mutant variants of p53, but not depletion of endogenous wild-type p53, promoted survival and cell-cell aggregation under conditions of cell detachment, leading to the formation of spheroids with mesothelium-clearing capacity. These phenotypes were blocked by mutant p53 reactivation and depended on the expression of the mesenchyme transcription factor TWIST1, inhibition of p63 and de novo formation of a unique cell-matrix adhesion niche supported by autocrine fibronectin production and activation of integrins in detached cells. Inhibition of fibronectin or integrin α5 in suspension blocked cell-to-cell adhesion leading to HGS-OvCa spheroid disintegration and ultimately anoikis. These results indicate the detached FTE cells-expressing GOF mutants of p53 undergo a mesenchymal transition under conditions of matrix detachment leading to autocrine production of matrix and anchorage-independent survival and proliferation, as well as mesothelial clearance activity. These findings provide important new insights into activities of mutant p53 that may play a critical role in early events in tumorigenesis of high-grade ovarian serous tumors and provide a rationale for the development of therapeutics that target ovarian cancer cells transiting through the peritoneal cavity.
This abstract is also presented as Poster B03.
Citation Format: Marcin P. Iwanicki, Hsing-Yu Chen, Ioannis Zervantonakis, Marian Novak, Taru Muranen, Tan A. Ince, Ronny Drapkin, Joan S. Brugge. Mutant p53 drives early events in fallopian tube tumorigenesis through mesenchyme-associated autocrine production of matrix that supports survival and mesothelial intercalation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr PR12.
Abstract 21: Mutation profiling of patients with multiple primary cancers reveals some common genomic alterations in signaling pathways
Authors: Wang Ruoyu , Zhao Dewei , Wang Zhiqiang , Gu Xuesong , Wen Shu , Ji Xuening , Cao Hong , Yang Bin , Wu Fei , Zhong Jianguo , Li Nina , Liang Shanshan , Li Heming , Zhang Yuewei , Ding Yan 
Published: May 2016

Abstract
Multiple primary cancers in a single individual are rare and usually challenging for effective treatments. Identification common cancer gene driver mutations and targets for patients with multiple primary malignant cancers will offer potential opportunities for effective personalized treatment. We have collected and analyzed tumor tissue samples from patients diagnosed with multiple primary cancers including lung cancer, kidney cancer, prostate cancer, and bone cancer from the Affiliated Zhongshan Hospital of Dalian University. Deep sequencing of the tumor samples was performed using TruSeq Amplicon - Cancer Panel (TSACP) which covers 48 cancer genes with more than 200 mutation hotspots. We have found that TP53 (75%), PIK3CA (50%), KDR(50%), VHL(50%), KRAS (25%), , FGFR(30%), EGFR(25%), HER2(25%) and ATM (25%) mutations are among the most common gene alterations across different types of primary cancers, they share some common cancer signaling pathways. Missense exon variation(4.13%) , non-coding exone variation(2.8%), and frameshift variation (0.41%) are among the most frequent alterations for functional effects. Targeted and chemotherapies have been recommended for personalized cancer treatments and circulating tumor cells (CTC) enumeration was conducted to monitor the prognosis of therapeutic efficacy.
Citation Format: Ruoyu Wang, Dewei Zhao, Zhiqiang Wang, Xuesong Gu, Shu Wen, Xuening Ji, Hong Cao, Bin Yang, Fei Wu, Jianguo Zhong, Nina Li, Shanshan Liang, Heming Li, Yuewei Zhang, Yan Ding. Mutation profiling of patients with multiple primary cancers reveals some common genomic alterations in signaling pathways. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 21.
Abstract 31: A new research solution for circulating cell free DNA with short amplicons allow accurate detection of 70 COSMIC mutations at 1% detection limit
Authors: Mongan Ann , Chien Richard , Martinez-Alcantara Antonio , Hyland Fiona 
Published: May 2016

Abstract
Non-invasive determination of the resistance or recurrence of tumor development will allow for a safer, more cost effective method for cancer research. As circulating tumor DNA makes up only a small fraction of cell-free DNA (cfDNA) recovered from blood plasma, targeted sequencing offers an ideal tool for mutation detection. Furthermore, as cfDNA is more fragmented than genomic DNA, it presents new technical challenges. In particular, reports in the literature have shown that the majority of cfDNA fragment sizes fall between 120-200 bp, with a median length of 170 bp. Consistent with these reports, we observed an amplicon size dependent improvement in coverage with input samples containing high amounts of fragmented DNA (FFPE or cfDNA). To optimize for cfDNA selection, we have released an Ion AmpliSeq™ designer that offers amplicons of 100-140 bp in size. In this study we conducted a head-to-head comparison between short (100-140 bp) and long (135-175 bp) designs for the same set of targets. These two panels evaluate 1000 COSMIC hotspot mutations from 73 frequently mutated genes. We applied a protocol using magnetic beads to isolate cfDNA from one control (Coriel GM23485) and 3 cfDNA samples. We completed the molecular characterization of the isolated cfDNA using the multiplexing capabilities of Ion AmpliSeq™ library preparation and Ion PGM™ sequencer. Our results showed the short amplicon design led to an improvement of library yield that correlated with the amounts of fragmented DNA contained in the cfDNA samples. The shorter amplicon design also offered improved depth coverage and uniformity for fragmented DNA, while maintaining high performance with genomic DNA. Variant analysis of GM23485 with 70 known mutations at 1% allelic frequency showed &gt;95% positive predictive value with no false negative. In short, the bead-based cfDNA isolation protocol and short amplicon designs offer a simple sample preparation workflow to facilitate rapid mutation detection for cfDNA in cancer research.
Citation Format: Ann Mongan, Richard Chien, Antonio Martinez-Alcantara, Fiona Hyland. A new research solution for circulating cell free DNA with short amplicons allow accurate detection of 70 COSMIC mutations at 1% detection limit. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 31.
Abstract 35: Evolution of resistance to glucocorticoid receptor agonists
Authors: Dalin Simona , Zhao Boyang , Hemann Michael T. 
Published: May 2016

Abstract
Chemotherapy resistance is a major obstacle to curing cancer patients. Over 90% of metastatic tumors are resistant to chemotherapy, leading to treatment failure. Although glucocorticoid receptor agonists (GRAs) are a very commonly used class of component drugs in front-line combination chemotherapies for hematopoietic cancer, our understanding of its mechanism(s) of action and resistance are very limited. Here using a preclinical murine model of Burkitt's lymphoma, we investigated the mechanism of resistance to the glucocorticoid receptor agonist dexamethasone. Dose responses of dexamethasone on the parental Eμ-myc; Arf-null cell line revealed a consistently small population of persistent survivors, suggesting a pre-existing subpopulation with innate dexamethasone resistance. To further address the evolution and selection of these survivors in the presence of GRAs, we derived resistant cell lines in vitro by treating the parental cell line with dose escalating concentrations of dexamethasone. These resistant cell lines were expectedly cross-resistant to other GRAs. However, loss of expression of the glucocorticoid receptor (GR) was not observed – ruling out one possible resistance mechanism. To explore alternative or downstream pathways that may be implicated, we subsequently acquired dose responses against a broad set of targeted kinase inhibitors, and observed modest sensitivity to the HSP90 inhibitor 17-AAG. This suggests that the resistance mechanism could be related to HSP90's role of holding ligand-free glucocorticoid receptor (GR) in the cytoplasm. We are now re-evolving the parental populations, and deriving clonal populations to confirm this phenotype. A better understanding of how hematopoietic cancer cells evolve resistance to GCAs will lead to improved design of drug combinations for prolonged survival.
Citation Format: Simona Dalin, Boyang Zhao, Michael T. Hemann. Evolution of resistance to glucocorticoid receptor agonists. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 35.