bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA11: Promises and challenges of applying molecular profiles to lung cancer treatment and early diagnosis.
Authors: Wistuba Ignacio I. 
Published: August 2014

Abstract
The field of lung cancer molecular pathology is rapidly changing due to advances in our understanding of the molecular pathogenesis of tumors. In the past ten years, the identification of new molecular targets has provided unique opportunities to attack cancer with targeted therapies in a personalized manner. Recent advances in expanding the available non-small cell lung carcinoma (NSCLC) targeted therapies require the analysis of a broad panel of molecular abnormalities in tumor specimens, including gene mutations, amplifications, fusions and expression by applying different methodologies to frequently small tumor tissue (biopsy) and cell (cytology) samples. In addition, there is growing consensus that tumor tissue specimens must represent the setting of the disease to be treated, and increasingly, more tissue samples are being obtained for molecular testing of advanced, metastatic and chemo-refractory NSCLC tumors (e.g., MD Anderson BATTLE Lung Cancer Program). Currently available methodologies and technologies, including microarrays and next-generation sequencing, have variable applicability for the molecular and genomic analysis of these small specimens. Thus, the role of the pathologist is becoming increasingly important to adequately integrate routine histopathology assessments and molecular testing with clinical pathology for the most accurate tumor diagnosis and subsequent selection of the most appropriate therapy. In addition, applying high-throughput molecular methodologies currently used in studying established tumors to epithelial cell samples obtained from the airway of high-risk individuals and lung cancer patients is expanding our understanding of the early pathogenesis of lung cancer. Earlier studies have highlighted a field cancerization phenomenon in which histologically normal-appearing tissue adjacent to neoplastic and preneoplastic lesions display molecular abnormalities some of which are in common with those in the tumors. There is consensus that advances in the understanding of this field phenomenon will help to the development of biomarkers for early detection of and personalized chemoprevention of lung cancer.
Citation Format: Ignacio I. Wistuba. Promises and challenges of applying molecular profiles to lung cancer treatment and early diagnosis. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA11.
Abstract IA39: Squamous cell lung cancer 2014.
Authors: Hammerman Peter S. 
Published: August 2014

Abstract
Despite the robust progress in developing molecularly targeted therapies for patients with lung adenocarcinoma, patients with other types of lung cancer have not benefitted much to date from molecularly targeted therapy. While in the past this was due to a lack of knowledge of the molecular underpinnings of other lung cancer types, large-scale genomic surveys have now demonstrated that relevant and targetable genomic alterations can be found in all histologies of lung cancer. Here I discuss recent data from genomic analyses of squamous cell lung cancer, the second most common type of non-small cell lung cancer and describe potential therapeutic targets in this disease with an emphasis on Fibroblast Growth Factor Receptors. I will summarize preclinical and early clinical studies and discuss how further progress in targeted therapy for squamous cell carcinomas can be made.
Citation Format: Peter S. Hammerman. Squamous cell lung cancer 2014. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA39.
Abstract A11: Common links suggest a shared embryologic origin for pancreatic and ovarian mucinous tumors
Authors: Labidi-Galy Intidhar , Elias Kevin M. , Vitonis Allison F. , Hornick Jason L. , Doyle Leona A. , Hirsch Michelle S. , Cramer Daniel W. , Drapkin Ronny 
Published: August 2014

Abstract
Background: Mucinous ovarian tumors (MOT) have been linked to mucinous colorectal and appendiceal adenocarcinomas. However, recent molecular studies suggest MOT may share more in common with pancreatic mucinous cystic neoplasms (MCN). Commonalities between these seemingly disparate tumors are explored.
Methods: Epidemiologic features of MOT and mucinous gastrointestinal tumors were compared using the SEER database. Regional cases of 287 mucinous ovarian tumors were examined against 2,339 age-matched controls to delineate MOT risk factors. A case series of MCN was identified by chart review. Protein expression patterns among tumors were examined using seven immunohistochemical markers.
Results: SEER revealed that among GI neoplasms the epidemiology of MCN was most similar to MOT by age, race, and stage. MCN occurred almost exclusively in women, with a sex ratio of 19:1, compared to 1•1:1 and 1•2:1 for mucinous colorectal and appendiceal adenocarcinomas. In the case-control study, appendectomy and cervical conization did not reduce the risk of MOT, while smoking (OR 2•68, 95% CI 1•85-3•89, p&lt;0•001), was associated with an increased risk of MOT. Smoking was similarly common among MCN patients. Histologically, MOT and MCN were CK7+, CK20-, MUC2-, and CDX2-, whereas mucinous colorectal and appendiceal adenocarcinomas were CK7-, CK20+, MUC2+, and CDX2+.
Interpretation: Clinical and morphologic similarities between MOT and MCN suggest a common pathogenesis, potentially a shared precursor such as embryologic rests that stopped in the pancreatic buds during migration of the primordial follicles to the gonads during development. This implies mucinous ovarian tumors may originate from primordial follicles, not the ovarian surface epithelium, offering a novel explanation for their pathogenesis.
Citation Format: Intidhar Labidi-Galy, Kevin M. Elias, Allison F. Vitonis, Jason L. Hornick, Leona A. Doyle, Michelle S. Hirsch, Daniel W. Cramer, Ronny Drapkin. Common links suggest a shared embryologic origin for pancreatic and ovarian mucinous tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A11.
Abstract A19: Comparison of genomic alteration patterns between ovarian clear cell carcinoma and renal cell carcinoma
Authors: Asada Kayo , Koso Takahiro , Oda Katsutoshi , Uehara Yuriko , Yamamoto Shogo , Tatsuno Kenji , Ueda Hiroki , Kurikawa Reiko , Ikeda Yuji , Hiraike Osamu , Kawana Kei , Yano Tetsu , Osuga Yutaka , Fujii Tomoyuki , Aburatani Hiroyuki 
Published: August 2014

Abstract
Background: Ovarian clear cell carcinoma (OCCC) is a distinct histopathological subtype in epithelial ovarian cancer, and its pathological features and gene expression profiles are similar to those of clear cell renal cell carcinoma (ccRCC), including HIF pathway activation. Methods: We performed whole exome sequencing and/or SNP typing array in 45 OCCC clinical samples, and obtained the data of ccRCC from TCGA. Results: We identified several genetic mutations in SWI/SNF complex and PI3K/mTOR pathway, which had been reported in ccRCC, but not in OCCC. Mutations of ARID1A (BAF250a) were predominant in OCCC (55% vs 4%), whereas PBRM1 (BAF180) mutations were detected only in ccRCC at 35%. Mutations of PIK3CA (60% vs 3.0%) and the genetic alterations in the PI3K/mTOR pathway (65% vs 30%, p&lt;0.05 by Fisher's exact test) were more common in OCCC. Distinct from ccRCC, we did not detect any mutations in VHL and copy number losses at chr 3p in OCCC. Conclusions: Genetic alteration patterns in the SWI/SNF complex and the PI3K/mTOR pathway are distinct between OCCC and ccRCC. Our data suggest that targeting mTOR pathway might be a promising therapeutic strategy in OCCC, as well as in ccRCC.
Citation Format: Kayo Asada, Takahiro Koso, Katsutoshi Oda, Yuriko Uehara, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Reiko Kurikawa, Yuji Ikeda, Osamu Hiraike, Kei Kawana, Tetsu Yano, Yutaka Osuga, Tomoyuki Fujii, Hiroyuki Aburatani. Comparison of genomic alteration patterns between ovarian clear cell carcinoma and renal cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A19.
Abstract A2: Novel serum biomarkers for histotype specific ovarian cancer diagnosis
Authors: Lehtinen Laura , Iljin Kristiina , Hynninen Johanna , Auranen Annika , Haglund Caj , Grenman Seija , Carpén Olli 
Published: August 2014

Abstract
Current diagnostic methods for ovarian cancer include gynecological inspection, ultrasound-imaging and detection of the serum tumor marker CA-125. Even combined, these methods are insufficient in specificity and sensitivity for detection of early disease. Since the majority of ovarian carcinomas are of epithelial origin, the carcinogenesis has thought to be induced in the epithelial layer of the ovaries or fallopian tubes. However, recent findings indicate that many ovarian cancers originate from non-ovarian tissues and therefore different ovarian cancer histotypes should be regarded as distinct diseases. Currently the histotype of ovarian carcinomas can be determined only during surgery. There is an increasing need for more sensitive and specific biomarkers for ovarian cancer diagnosis as well as for prediction of biological tumor behavior.
In this study, genes with ovarian cancer specific expression profile were identified from publicly available gene-expression databases. In order to find potential serum biomarker candidates, further in silico data mining was performed utilizing the GeneSapiens database. The identified ovarian cancer specific and potentially secreted or surface-expressed genes were validated in vitro in patient samples and primary ovarian cancer cells lines with qRT-PCR, western blotting and immunohistochemical staining of tumor tissue microarrays. The presence of the candidate biomarkers in patient serum samples was studied with dot blotting and immunoprecipitation. Finally, the expression levels of the candidate genes were compared to the pre-operative CA-125 and HE-4 levels in a cohort of prospective collected advanced ovarian cancer patients.
The in silico data analyses resulted in identification of altogether six novel serum biomarker candidates for serous, mucinous and clear cell ovarian tumors. Analysis of tumor samples and primary cell lines derived from ovarian cancer patient samples confirmed the expression of the candidate genes in ovarian carcinomas. Furthermore, the mRNA analysis showed evidence of histotype specificity, especially in the case of potential biomarkers for mucinous ovarian carcinoma. Immunohistochemical staining of several tumor tissue samples showed distinctive cytoplasmic expression pattern characteristic for secreted proteins. Further analysis of the presence of the biomarkers in the sera of the patients and matched controls is in progress.
Citation Format: Laura Lehtinen, Kristiina Iljin, Johanna Hynninen, Annika Auranen, Caj Haglund, Seija Grenman, Olli Carpén. Novel serum biomarkers for histotype specific ovarian cancer diagnosis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A2.
Abstract A25: PPP2R1A mutations affect PP2A complex formation, and novel protein interactions in gynecological carcinoma cell lines
Authors: McConechy Melissa K. , Chen Vincent , Morin Gregg , Brenton James , Huntsman David G. 
Published: August 2014

Abstract
Gynecological malignancies (ovarian clear cell and endometrioid carcinomas, endometrial serous, endometrioid and clear cell carcinomas) harbor somatic mutations in the gene PPP2R1A, the scaffolding subunit of the serine/threonine protein phosphatase 2A (PP2A) complex. The PP2A complex is composed of an A (scaffold), C (catalytic) subunit, and different B (regulatory) subunits. The PPP2R1A mutations are proposed to play a role in PP2A B-subunit binding, and thus formation of a functional PP2A phosphatase complex. The aim of this study is to determine how PPP2R1A mutations affect the binding of B-subunits and other novel interactions within the context of ovarian and endometrial carcinomas.
The ovarian clear cell line RMG2 and endometrial carcinoma cell lines Hec-1-A and Hec50 all harbor PPP2R1A mutations. The mismatch repair deficient cell line Hec-1-A express a PPP2R1A W257L heterozygous mutation; therefore somatic cell knockout technology was used to generate isogenic PPP2R1A clones that express only mutant PPP2R1A, and clones that express more wild-type than mutant. These Hec-1-A isogenic cell lines were used for PPP2R1A co-immunoprecipiation (Co-IP) followed by MS/MS-SWATHTM analysis to identify PP2A B-subunits and other novel protein interactions.
Our preliminary results using Hec-1-A isogenic cell lines suggest that some PP2A B-subunits (PPP2R5D and PPP2R2A) are found to be decreased in abundance in the mutant cell lines. We were able to identify the catalytic subunit (PPP2CA) in PPP2R1A Co-IPs in all cell lines. We also show that PPP2R1A interacts with novel proteins such as histones (Histone 1, Histone H2B type 1-N), ubiquitin ligases (TRIM21) and proteins involved in mitotic control (ANKLE2). Of particular interest we have identified the cancer gene nucleophosmin (NPM1) as a potential novel interactor of PP2A.
We have established the isogenic Hec-1-A cell lines as a model system to determine the functional effects of a somatic PPP2R1A mutation. These cell lines have shown that the PPP2R1A mutation affects the ability of some B-subunits to interact and form the PP2A complex. We have also shown that PP2A may interact with novel proteins such as NPM1 and histones. Ongoing work will be completed to determine how these interactions function in the context of ovarian and endometrial carcinomas.
Citation Format: Melissa K. McConechy, Vincent Chen, Gregg Morin, James Brenton, David G. Huntsman. PPP2R1A mutations affect PP2A complex formation, and novel protein interactions in gynecological carcinoma cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A25.
Abstract A36: Protein markers of tumor-initiating cells and mitochondrial function in ovarian cancer
Authors: Gabrielson Marike , Björklund My , Carlson Joseph , Shoshan Maria 
Published: August 2014

Abstract
Background: Epithelial ovarian carcinoma (EOC) is the 5th leading cause of total cancer death in women. Despite initial responsiveness to treatment, &gt;75% of patients relapse into metastatic and essentially incurable chemoresistant disease. In carcinomas, metastasis is associated with the dedifferentiation process termed epithelial-to-mesenchymal transition (EMT). EMT is molecularly related to a cancer stem cell phenotype. Cancer stem cells, or tumor-initiating cells (TICs) as they are now called, are increasingly believed to underlie relapse, and are by definition highly chemoresistant and able to give rise to metastases. By repeated cisplatin treatment of the EOC cell line SKOV-3, originating from malignant ascites, we have created a stable subline (SKOV-3-R) expressing TIC markers, and showing EMT, increased motility, sphere formation in stem cell medium. They also show increased mitochondrial content and expression of mitochondrial VDAC, and hexokinase-II (HK-II) known to be upregulated in glycolytic tumor cells [1]. The chemoresistance of SKOV-3-R was found to depend on HK-II [1]. The role of altered mitochondrial functions in tumor progression and in TICs is attracting increased attention.
Aim: To examine and correlate expression of TIC markers and mitochondrial markers in clinical samples, and to relate these to EOC subtype and hormone receptor status.
Results: SKOV-3-R expresses TIC markers CD117, CD44 and ALDH1. Cells freshly isolated from malignant EOC ascites were analysed for TIC markers CD117, CD44, EpCAM and Nanog, and loss of E-cadherin as a marker of EMT. In an immunohistochemical pilot study on 60 patient samples we now examine expression of CD117, CD44, ALDH1, and VDAC and HK-II.
Discussion: The SKOV-3-R results indicate that these cells constitute an in vitro model of TICs and that they have increased mitochondrial content. The analysis of malignant ascites shows potentially high levels of TICs in ascites. Results of immunhistochemical analysis of tumors are pending (August, 2013).
1. Wintzell M, Lofstedt L, Johansson J, Pedersen AB, Fuxe J, Shoshan M: Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate. Cancer Biol Ther 2012, 13(14):1454-1462.
Citation Format: Marike Gabrielson, My Björklund, Joseph Carlson, Maria Shoshan. Protein markers of tumor-initiating cells and mitochondrial function in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A36.
Abstract A52: Targeting c-MYC in cisplatin-resistant ovarian cancer
Authors: Reyes Jeyshka , Ivan Cristina , Sood Anil K. , Vivas-Mejia Pablo E. 
Published: August 2014

Abstract
Cisplatin has been the most active drug for the treatment of ovarian cancer for the last four decades. Although the majority of patients with ovarian cancer respond to front-line platinum combination chemotherapy, relapse occurs in over 70% of patients, resulting in chemoresistant, fatal disease. Therefore, there is an urgent need to find new therapies focused on targets within cancer cell survival pathways for advanced stage drug resistant ovarian cancer. Evidence indicates that activation of the oncogenic transcription factor c-MYC is involved in such resistance. Furthermore, it has been found that there is a significant association between increasing c-MYC expression and poor survival. Our previous findings indicate that cisplatin-resistant cells express higher c-MYC protein levels when compared to their sensitive counterparts. Importantly, targeting of c-MYC with small interference RNA (siRNA) in the cisplatin-resistant ovarian cancer cell line, A2780CP20, induced a significant cell growth arrest and inhibition of cell proliferation. Apoptosis and arrest of cell cycle progression were also observed after siRNA-based silencing of c-MYC. The mRNA expression of c-MYC and clinical data for 373 patients with high grade serous ovarian cancer were downloaded from “The Cancer Genome Atlas” (TCGA) data portal. The log-rank test revealed a significant relationship between the expression of c-MYC and the time of progression/recurrence of the tumor. These data suggests c-MYC as a potential therapeutic target for overcoming cisplatin resistance in ovarian cancer.
Citation Format: Jeyshka Reyes, Cristina Ivan, Anil K. Sood, Pablo E. Vivas-Mejia. Targeting c-MYC in cisplatin-resistant ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A52.
Abstract A62: Imaging the tumor micro-environment to monitor ovarian cancer metastasis
Authors: Slack-Davis Jill K. , Scalici Jennifer M. , Thomas Stephanie , Harrer Christine , Raines Timothy A. , Curran Joanna , Atkins Kristen A. , Conaway Mark R. , Duska Linda , Kelly Kimberly A. 
Published: August 2014

Abstract
The inability to successfully treat women with ovarian cancer is due in large part to the advanced stage of disease at diagnosis, the development of platinum resistance, and the lack of sensitive methods to monitor tumor progression and response to treatment. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on the mesothelium of ovarian cancer patients. We investigated VCAM-1 expression as a marker of peritoneal metastasis and tumor response to platinum-based chemotherapy. Immunohistochemical staining of peritoneal or omental biopsies obtained from women diagnosed with Stage I, Stage II or Stage III/IV ovarian cancer demonstrated that VCAM-1 expression correlated with tumor stage. All specimens from Stage I patients were negative, while 29% of Stage II patients and the 73% of Stage III/IV patients were positive. While the majority of women with advanced stage disease expressed VCAM-1, the incidence of expression was reduced among women who received neoadjuvant chemotherapy, suggesting a role for chemotherapy in regulating VCAM-1 expression. The effects of carboplatin on mesothelial VCAM-1 expression were determined in a mouse model of ovarian cancer peritoneal metastasis using radiolabeled VCAM-1-specific peptide imaging probes and single photon emission computed tomography (SPECT). This approach showed that 1) VCAM-1 is a viable imaging target in ovarian cancer metastasis, 2) maximal expression was detected with microscopic tumor burden, and 3) VCAM-1 expression reflected the effect of platinum-based treatment on tumor burden. Specifically, carboplatin treatment of mice with platinum-sensitive tumors showed reduced VCAM-1 expression, which correlated with reduced tumor burden; mice with platinum-resistant tumors retained elevated VCAM-1 expression and tumor burden following treatment. These observations support testing the utility of VCAM-1 imaging probes to monitor treatment response in ovarian cancer patients, thus providing the potential to improve management of women with this disease.
Citation Format: Jill K. Slack-Davis, Jennifer M. Scalici, Stephanie Thomas, Christine Harrer, Timothy A. Raines, Joanna Curran, Kristen A. Atkins, Mark R. Conaway, Linda Duska, Kimberly A. Kelly. Imaging the tumor micro-environment to monitor ovarian cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A62.