bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract POSTER-CTRL-1206: The mutational landscape of fallopian tube carcinoma
Authors: Harrell M.I. , Walshb T. , Agnew K.J. , Norquist B. , Lee M.K. , Bernards S. , Pennington K.P. , Swisher E.M. 
Published: August 2015

Abstract
Fallopian tube (FT) carcinoma is a rare gynecological malignancy, whose incidence is most likely underestimated due to misdiagnoses as ovarian cancer. Recent advances in pathology with more thorough serial sectioning techniques have led to better identification. We undertook to define germline and somatic mutations in 98 FT carcinoma cases enrolled at diagnosis in IRB-approved studies at the University of Washington, excluding cases with carcinoma identified at the time of risk-reducing surgery. We sequenced DNA from blood and neoplastic tissue using BROCA, a targeted capture and massively parallel genomic sequencing approach that detects all classes of mutation in 64 genes. The fraction of all primary ovarian, peritoneal and FT carcinoma defined as a FT primary increased over time in our tissue bank: FT diagnoses accounted for 23% of cases in the past five years compared to 5% in the previous 10 years (p=0.002). Of 98 subjects with FT carcinoma, 32 (33%) had loss of function germline mutations in 9 genes. Mutations in BRCA1 were identified in 18 (19%), making up the largest number of germline mutations, and in BRCA2 in 4 (4%). Germline mutations were also identified in 6 other known breast and/or ovarian cancer susceptibility genes including 2 in BRIP1 (2%), 2 in CHECK2 (2%), and 1 each in BARD1, BLM, MRE11A, and ATM (1%). One mutation was found in the FA gene FANCL. Additionally, we found 1 mosaic mutations in TP53 (1%) and 2 in PPM1D (2%). Together germline and mosaic mutations were identified in 34 (35%) of cases. We sequenced neoplastic DNA with BROCA in 30 FT carcinomas and found 27 somatic mutations in TP53 (90%), 1 in PTEN (3%) and 1 in CHEK2 (3%). The germline mutation rate was higher in FT carcinoma compared to our previous studies in ovarian carcinoma (35% versus 22%), though the identified genes were similar. Recently identified ovarian cancer susceptibility genes such as BRIP1, BARD1, and PPM1D are also associated with hereditary fallopian tube cancer. Known breast cancer genes (i.e. CHEK2, MRE11A, ATM) and other cancer associated genes (BLM, FANCL) require further study to prove their association with FT or ovarian cancer risk. An increased pathological recognition of the FT as a primary site of disease is changing the relative distribution of FT, ovarian, and peritoneal carcinoma in some centers.
Citation Format: M.I. Harrell, T. Walshb, K.J. Agnew, B. Norquist, M.K. Lee, S. Bernards, K.P. Pennington, E.M. Swisher. The mutational landscape of fallopian tube carcinoma [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1206.
Abstract POSTER-CTRL-1214: Systematic identification of high risk women for genetic counseling and surgical prevention of ovarian cancer
Authors: Resta Robert , Drescher Charles W. , Beatty David , Andersen M Robyn , Watabayashi Kate , Thorpe Jason , Purkey Hannah , Chubak Jessica , Hanson Nancy , Buist Diana S.M. , Urban Nicole 
Published: August 2015

Abstract
Objectives: Information technology provides an opportunity for systematic identification of high-risk patients for appropriate referral. We conducted a randomized controlled trial to test whether routine identification of women at high risk for epithelial ovarian cancer using an electronic database and subsequent referral to genetic counseling would promote genetic testing and prophylactic surgery.
Methods: Electronic data in a mammography reporting system from a large community hospital in Seattle was used to identify women at increased risk for ovarian cancer based on personal and family cancer history. Following secondary confirmation of eligibility and consent, women were randomly assigned to an intervention consisting of a genetic counseling referral, or to standard clinical care.
Results: A total of 458 women were enrolled. Compared to standard clinical care systemic identification and referral of high risk women to genetic counseling increased the number of women who elect to undergo genetic testing (75 vs 20, p&lt;0.005) and prophylactic surgery (OR: 3.5, p=0.05).
Conclusions: Our results demonstrated that systematic identification of high-risk women for referral to genetic counseling is feasible and increases utilization of risk-appropriate prevention strategies.
Citation Format: Robert Resta, MS CGC; Charles W. Drescher, MD; David Beatty, MD; M Robyn Andersen, PhD; Kate Watabayashi, BA; Jason Thorpe, MSc; Hannah Purkey, BS; Jessica Chubak, PhD; Nancy Hanson, MS CGC; Diana S.M. Buist, MPH PhD; Nicole Urban, ScD. Systematic identification of high risk women for genetic counseling and surgical prevention of ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1214.
Abstract POSTER-CTRL-1216: Profile of BRCA testing in ovarian cancer patients in the US and EU
Authors: Tyczynski JE , Moss S , De Richter P 
Published: August 2015

Abstract
Purpose: Around 13% of patients with ovarian cancer harbor mutations in the BRCA genes. Their disease has distinct characteristics which may impact treatment pathways. However, currently only a selected subset of ovarian cancer patients are offered testing for BRCA mutation, based largely upon family history of BRCA-related tumors. Frequencies of, and barriers to testing are not well characterized; therefore, our objective was to describe the current BRCA testing practices among women diagnosed with ovarian cancer.
Methods: A survey of 465 oncologists, 513 pathologists and 97 laboratory directors, including detailed questionnaires for 435 ovarian cancer patients, across the US, UK, France, Germany, Italy and Spain was conducted during 2013 by Ipsos Healthcare syndicated MDx Monitor.
Results: Physician awareness of BRCA testing in ovarian cancer patients varies: 61–86% in EU and over 90% in US. 50–67% of oncologists in EU, compared with over 80% in US, claim to have used BRCA testing within 6 months from diagnosis. On average, between 24% (US) to 7% (UK) of ovarian cancer patients were tested for BRCA post-diagnosis with large variations between physicians. Guidelines and patient requests were drivers for testing; barriers included perceived lack of clinical utility/targeted therapies (~35%), lack of BRCA risk factors (~5–70% depending on country), patient refusal (~5%), and reimbursement/cost (~15%). In all markets, both germline and somatic BRCA testing were common. Testing was generally performed in remote laboratories for efficiency. In US, most testing was conducted by Myriad; in EU several different tests, including 5% that were developed locally (by individual laboratories), were used.
Conclusions: While there is broad knowledge and use of BRCA testing, the survey has highlighted significant barriers which may prevent ovarian cancer patients from being offered the test. Ongoing research aims to demonstrate the value of testing a broader cohort of patients, to identify individuals who may benefit from more personalized treatment approaches.
Citation Format: Tyczynski JE, Moss S, De Richter P. Profile of BRCA testing in ovarian cancer patients in the US and EU [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1216.
Abstract POSTER-TECH-1119: Phylogenetic portraits of high grade serous ovarian cancer
Authors: McPherson Andrew , Roth Andrew , Huntsman David , McAlpine Jessica , Shah Sohrab 
Published: August 2015

Abstract
High Grade Serous Ovarian Cancer (HGSOvCa) is characterized by genomic instability resulting from deficient DNA repair processes primarily due to TP53 mutation and BRCA abnormalities. Genomic instability has been shown to result in significant intratumoral heterogeneity, with temporally and spatially separated tumours exhibiting unique mutational profiles. A key unanswered question is whether genomic instability produces functionally relevant driver mutations, or whether the tumours complement of driver mutations predates the emergence of instability.
We sought to reconstruct the evolutionary histories of the tumours of 8 HGSOvCa patients using spatial and temporal profiling of somatic mutations. For each patient, we collected multiple tumour biopsies resected from primary and metastatic sites at the time of surgery. We then used whole genome shotgun sequencing to identify somatic point mutation, rearrangement and copy number changes present at each site. We used novel computational techniques to unmix the signal produced by sequencing of a mixture of tumour cells, and infer the genomic architecture of clonal populations in each tumour sample. Additionally, we used phylogenetic inference techniques to reconstruct the ancestral relationships between the genomically distinct clones identified in each patient. We classified mutations as occurring ancestrally (before clonal divergence) or occurring on a descendent lineage.
We identified multiple well known driver mutations occurring in descendent lineages of the tumour phylogeny, including mutations in CDKN2A, BCL6 and ERBB2. Aberrant site specific expression patterns were concomitant with genomic changes. Furthermore, we identified instances of convergent evolution, including independent deletion of wild type RAD51B in a patient with a germline RAD51B mutation. Reconstruction of clonal phylogenies enabled inference of metastatic spread. In one patient, a minor subclone of a right ovary tumour acquired an ERBB2 amplification, then subsequently populated all other metastatic sites sampled by the experiment. Finally, from our analyses we concluded that in many HGSOvCa, genomic instability and associated copy number changes result in the deletion of a significant number of point mutations, with implications for phylogenetic reconstruction using traditional techniques.
Citation Format: Andrew McPherson, Andrew Roth, David Huntsman, Jessica McAlpine, Sohrab Shah. Phylogenetic portraits of high grade serous ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1119.
Abstract POSTER-TECH-1130: Identification of putative genes involved in early steps of epithelial ovarian cancer pathogenesis
Authors: Tamimi Yahya , Burney Ikram , Al-Kalbani Moza , Lakhtari Ritu , Godbout Roseline , Al-Moundhri Mansour 
Published: August 2015

Abstract
Epithelial ovarian cancer (EOC) is a deadly q disease and the related statistics are alarming with 15000 lives claimed in USA each year. EOC is a subtle disease since the majority of patients at presentation are diagnosed with a higher stage disease characterized by an aggressive potential. Early diagnosis seems to be of importance since complete cure can reach up to 90% if the disease is diagnosed at an early stage. Therefore, biological markers to detect patients at an early stage of the disease progression are urgently needed. In this study, the focus was centered on the transcription factor E2F5 used as biomarker and highly expressed at early stages of EOC pathogenesis. Therefore, we hypothesize that downstream genes regulated by this transcription factor might be also involved in the early events leading to ovarian cancer and can therefore potentially serve as useful biomarkers.
Chromatin Immuno-Precipitation (ChIP) was performed using two ovarian cancer cell lines SK-OV-3 and OVCAR-3 and an antibody against E2F5 transcription factor.
The enriched chromatin was cloned and sequenced before using available databases for BLAST and identification of downstream regulated genes.
A short list of relevant genes, all involved in cancer, was obtained and analysis for their putative role in early detection of EOC is ongoing. The selected genes will be also validated using frozen human ovarian tissues available in our institution.
ChIP is a robust technology to identify genes regulated by E2F5 with a putative potential to play a crucial role in the early steps of ovarian cancer pathogenesis.
Citation Format: Yahya Tamimi, Ikram Burney, Moza Al-Kalbani, Ritu Lakhtari, Roseline Godbout, Mansour Al-Moundhri. Identification of putative genes involved in early steps of epithelial ovarian cancer pathogenesis [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1130.
Abstract POSTER-THER-1403: FZD7 drives aggressiveness in stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway
Authors: Asad Mohammad , Kang Wong Meng , Zea Tan Tuan , Choolani Mahesh , Low Jeffery , Mori Seiichi , Thiery Jean Paul , Huang Ruby Yun-Ju 
Published: August 2015

Abstract
Ovarian cancer (OC) can be classified into five biologically distinct molecular subgroups—Epi-A, Epi-B, Mes, Stem-A and Stem-B. Among them, Stem-A expresses genes relating to stemness and is correlated with poor clinical prognosis. In this study, we show that FZD7, a receptor for Wnt signalling, is overexpressed in the Stem-A subgroup. To elucidate the functional roles of FZD7, we used an RNA interference (RNAi) gene knockdown approach in three Stem-A cell lines: CH1, PA1 and OV-17R. Si-FZD7 OC cells showed reduced cell proliferation with an increase in the G0/G1 subpopulation, with no effect on apoptosis. The cells also displayed a distinctive morphological change by colony compaction to become more epithelial-like and polarised with smaller inter-nuclear distances and increased z-axis height. Immunofluorescence (IF) staining patterns of pan-cadherin and β-catenin suggested an increase in cadherin-based cell-cell adhesion in si-FZD7 cells. We also observed a significant rearrangement in the actin cytoskeleton and an increase in tensile contractility in si-FZD7 OC cells, as evident by the loss of stress fibres and the redistribution of phospho-myosin light chain (pMLC) from the sites of cell-cell contacts to the periphery of cell colonies. Furthermore, there was reciprocal regulation of RhoA and Rac1 activities upon FZD7 knockdown, with a significant reduction in RhoA activity and a concomitant up-regulation in Rac1 activity. These changes in pMLC and RhoA as well as the increased TOPFLASH reporter activities in si-FZD7 cells suggested involvement of the non-canonical Wnt/planar cell polarity (PCP) pathway. Selected PCP pathway genes (CELSR3, PRICKLE4, DAAM1, PFN2, PCDH9, PCDHA1, PCDHB17, PCDHB3, SPRY1, and PTK7) were found to be more highly expressed in Stem-A than non Stem-A subgroup of OC. Taken together, our results suggest that FZD7 might drive aggressiveness in Stem-A OC by regulating cell proliferation, cell cycle progression, maintenance of the mesenchymal phenotype, and cell migration via CK1ϵ-mediated non-canonical Wnt/PCP pathway.
Citation Format: Mohammad Asad, Wong Meng Kang, Tan Tuan Zea, Mahesh Choolani, Jeffery Low, Seiichi Mori, Jean Paul Thiery, Ruby Yun-Ju Huang. FZD7 drives aggressiveness in stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1403.
Abstract POSTER-THER-1418: PD-1 mediated paralysis of ovarian cancer infiltrating dendritic cells
Authors: Karyampudi Lavakumar , Krempski James , Lamichhane Purushottam , Kalli Kimberly R. , Behrens Marshall D. , Vargas Doris M. , Hartmann Lynn C , Hedin Karen E , Goode Ellen L. , Knutson Keith L. 
Published: August 2015

Abstract
Purpose: It is well known that the immune system impacts the clinical course of ovarian cancer suggesting that immune-based approaches may effective in treating the disease. This has led to several clinical trials of novel treatments such as antibody, vaccine, and adoptive T cell therapy. PD-1:PD-L1 axis is a major immune regulatory pathway that blunts immune effectors in the tumor microenvironment. It is well known that high surface expression of PD-1 on tumor infiltrating T cells is a sign of their exhaustion. However, the complete mechanism behind the PD-1 regulation of T cell exhaustion is yet to be explored. Recently we identified that PD-1 is also expressed on ovarian tumor-infiltrating myeloid dendritic cells (DCs) that exhibit an immunosuppressive phenotype. Our goal in this study was to understand the mechanism by which PD-1 mediates the paralysis of ovarian cancer infiltrating DCs.
Experimental procedures: PD-1+ DCs obtained from ID8 mouse model of ovarian cancer were used in this study. Data from this preclinical model was confirmed by using myeloid DCs obtained from ovarian cancer patient’s samples. Using standard flow cytometry, immunoassays (ELISA, multiplexed cytokine assay), PCR array, western blot and confocal microscopy, PD-1 mediated paralysis of ovarian cancer DCs was determined.
Results: Our data shows that blockade of surface PD-1 on ovarian cancer infiltrating DCs results in their activation by, enhancing their surface co-stimulatory molecules expression, increasing their motility, enhancing their antigen presentation capacity, and increasing their production of immunostimulatory cytokines. Also, our results suggest that PD-1 expressed on tumor DCs mediates the suppression of NFkB which occurs through SHP-2 and IKK dependent mechanisms.
Conclusion: Our study reveals that blockade of PD-1 on ovarian cancer infiltrating DCs results in the reversal of their paralysis to such an extent that it overrides their B7-H1 mediated suppression of T cells and this occurs through the reversal of PD-1 mediated tonic suppression of NFkB.
Citation Format: Lavakumar Karyampudi James Krempski, Purushottam Lamichhane, Kimberly R. Kalli, Marshall D. Behrens, Doris M. Vargas, Lynn C Hartmann, Karen E Hedin, Ellen L. Goode, Keith L. Knutson. PD-1 mediated paralysis of ovarian cancer infiltrating dendritic cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1418.
Abstract POSTER-THER-1428: Effects of atypical PKC inhibitors on ovarian cancer proliferation and RNA levels
Authors: Shah Minjel , Apostolatos Christopher , Apostolatos Hercules , Acevedo-Duncan Mildred 
Published: August 2015

Abstract
Ovarian cancers are highly lethal tumors which account for approximately four percent of all women’s cancers and are the fifth leading cause of cancer-related death among women. At diagnosis the majority of patients have metastatic disease and the long-term survival remains low. Certain ovarian cancers are highly lethal tumors due to the emergence of therapy-resistant ovarian cancer cells. Protein kinase C-iota (PKC-ι) has been shown to aid in the ability of cancer cells to resist drug-induced apoptosis. Recently, it has been reported that PKC-ι which is located in chromosome 3 at 3q26.2 is the most common genomic amplicon as identified by comparative genomic hybridization [Proc Natl Acad Sci U S A 102:12519–12524(2005)]. Additionally, an increase in PKC-ι DNA copy number was associated with decreased progression-free survival of ovarian cancer patients. Moreover, only PKC-ι gene amplification is highly correlated with protein overexpression, tumor size, lymph node metastasis and clinical stage out of four genes studied on the 3q26 amplification [Genes Chromosomes Cancer 47:127-136(2008)]. The focus of this research was to determine the in-vitro efficacy of the pan-atypical PKC inhibitor, 2-acetyl-1,3-cyclopentanedione (ACPD; Diabetes. 2014 Apr 4) and the novel PKC-iota inhibitor, ICA-1, (1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy) methyl]cyclopentyl]-,[1R-(1α, 2β, 3 β, 4 α) [The Inter. J. Biochem. & Cell Biol. 43:784-794(2011)] on HEY ovarian cancer cell proliferation and RNA concentration. In contrast to ACPD which inhibits both PKC-ι and PKC-zeta (PKC-ζ), ICA-1 specifically inhibits the activity of PKC-ι but not (PKC-ζ). The effects of ACPD and ICA-1on HEY proliferation was quantified by Trypan blue exclusion assay. RNA was isolated from treated and untreated cells using the Rneasy Mini Kit and protocol. Total RNA concentration was estimated using the NanoDrop1000 Spectrophotometer. Results showed that incubation of HEY ovarian cancer cells with ICA-1(1 μm) decreased proliferation by 41% compared to controls at 72 hours post-treatment. ICA-1(2 μM) reduced RNA levels by 17% at 72 hours post-treatment compared to controls. In contrast, ACPD (2 μM) inhibited proliferation by 82% compared to controls and RNA levels were reduced by 97% at 24 hours post-treatment. These results suggest the potential of ICA-1 and ACPD as chemotherapeutic agents.
Citation Format: Minjel Shah, Christopher Apostolatos, Hercules Apostolatos, Mildred Acevedo-Duncan. Effects of atypical PKC inhibitors on ovarian cancer proliferation and RNA levels [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1428.
Genetic Determinants of Unruptured Intracranial Aneurysms in the General Population
Authors: Peymani Abbas , Adams Hieab H.H. , Cremers Lotte G.M. , Krestin Gabriel , Hofman Albert , van Duijn Cornelia M. , Uitterlinden André G. , van der Lugt Aad , Vernooij Meike W. , Ikram M. Arfan 
Published: August 2015

Background and Purpose—
Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for intracranial aneurysms in clinical samples. In addition, SNPs have been discovered for blood pressure, one of the strongest risk factors for intracranial aneurysms. We studied the role of these genetic variants on occurrence and size of unruptured intracranial aneurysms, discovered incidentally in a general community-dwelling population.

Methods—
In 4890 asymptomatic participants from the Rotterdam Study, 120 intracranial aneurysms were identified on brain imaging and segmented for maximum diameter and volume. Genetic risk scores (GRS) were calculated for intracranial aneurysms (10 SNPs), systolic blood pressure (33 SNPs), and diastolic blood pressure (41 SNPs).

Results—

The GRS for intracranial aneurysms was not statistically significantly associated with presence of aneurysms in this population (OR, 1.16; 95% CI, 0.96–1.40;
P
=0.119), but showed a significant association with both maximum diameter (difference in log-transformed mm per SD increase of GRS, 0.10; 95% CI, 0.02–0.19;
P
=0.018) and volume (difference in log-transformed µL per SD increase of GRS, 0.21; 95% CI, 0.01–0.41;
P
=0.040) of aneurysms. GRSs for blood pressures were associated with neither presence nor size of aneurysms.

Conclusions—
Genetic variants previously identified for intracranial aneurysms in clinical studies relate to the size rather than the presence of incidentally discovered, unruptured intracranial aneurysms in the general population.