bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1674: Prediction of survival based on tumor size dynamics and new lesions in EGFR mutation-positive non-small cell lung cancer patients treated with gefitinib or carboplatin and paclitaxel
Authors: Dunyak James , Buros-Novik Jacqueline , Novik Eric , Yan Hong , Al-Huniti Nidal 
Published: August 2019

Abstract
Objectives: Dynamics of tumor size have long been used for the clinical diagnosis, staging, prognosis and treatment of non-small cell lung cancer (NSCLC). The aim of this work was to develop a joint statistical framework to interrogate the longitudinal tumor burden, the appearance of new lesions, and changes in therapy following progression in a population of NSCLC patients treated with an EGFR inhibitor gefinitib to predict, given early results, time to progression (PFS) and overall survival at both population and individual levels.
Methods: The model builds on a previously developed joint model for tumor size and survival. The tumor size model was extended to estimate the probability of a new lesion. For the survival submodel, two additional biomarkers were evaluated: the derivative of the sum of longest diameters (SLD) and the probability of new lesions. The model was fitted in a Bayesian framework using STAN. Model was developed from 434 EGFR+, NSCLC patients treated with gefitinib or carboplatin+paclitaxel (‘IPASS’, NCT00322452). Predictive performance was evaluated on a cohort of 102 EGFR+ NSCLC patients (‘IFUM’, NCT01203917).
Results: Overall, the model fit well to the observed data and the predictive performance was strong in both within- and out-of-sample evaluations. Surprisingly, SLD derivative and new-lesion association parameters appear to negatively impact model performance, indicating further improvement of these submodels might be necessary. The model recapitulates response evaluation criteria in solid tumors (RECIST) outcomes with nearly 90% accuracy. When comparing progression-specific hazards, it appears the drug effect is mediated by tumor size dynamics rather than new lesion incidence.
Conclusion: This Bayesian joint model of tumor size and survival accurately recapitulates the RECIST-based outcomes and generates well calibrated predictions of survival. It offers insights regarding the relative predictive value of the components of RESICT in NSCLC.
Citation Format: James Dunyak, Jacqueline Buros-Novik, Eric Novik, Hong Yan, Nidal Al-Huniti. Prediction of survival based on tumor size dynamics and new lesions in EGFR mutation-positive non-small cell lung cancer patients treated with gefitinib or carboplatin and paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1674.
Abstract 1678: Accurate detection of expressed variation in RNA-seq
Authors: Mose Lisle E. , Marron David , Parker Joel S. 
Published: August 2019

Abstract
Somatic variant detection has long been an area of great interest and critical importance in cancer research and treatment. DNA-Seq based somatic variant calling pipelines have been maturing over the last several years and although there is still room for improvement, several methods have been developed capable of accurately detecting somatic variants from matched tumor/normal DNA. RNA-Seq has become a widely used tool for measuring gene and isoform abundance, identifying alternative splicing, and detection of gene fusions. Detection of expressed variation is receiving growing interest, however computational methods to detect this variation have received far less attention than that of DNA-Seq. We have developed an optimized RNA-Seq pipeline based upon the ABRA2 realigner capable of accurately detecting expressed somatic variation in RNA-Seq.
We applied this pipeline to the TCGA Breast Cancer dataset. To assess the impact of identification of expressed variation as an indicator of variant significance, we compared the expression state of the top 20 cohort wide significantly mutated genes (SMG) as identified by The Cancer Genome Atlas Network (2012) with all other genes. At the median for SMGs, 23 somatic variants are expressed with over 90% of variants detected in DNA being expressed. For non-SMGs, the median number of expressed variants is 1 and the median fraction of expressed variants is 50%. Among non-SMGs, a total of six genes exceed the median total number of expressed variants and fraction of expressed variants for SMGs (AHNAK, CHD4, ERBB2, FASN, FOXA1 and MYH9). All of these variants have been previously implicated in breast cancer, however none of these variants were among the cohort wide SMGs identified in the original study and only FOXA1 was identified as being a subtype specific SMG (ER+,ER+/HER2-). Notably, variants in the massive TTN gene are found to be coding 73% of the time, but expressed in only 8% of cases. This is substantially less than the 90% found in SMGs and a likely indicator that TTN mutations are passenger variants. The median and third quartile RNA variant allele frequency (VAF) for SMGs is .41 and .69 versus .32 and .46 for DNA. By comparison, the median and third quartile VAF for non-SMGS was 0 and .27 in RNA and .20 and .30 for DNA. The increased VAF for RNA SMGs is a likely indicator of selection and can potentially further be used to identify variants of significance. We believe these results demonstrate the utility of variant expression as a potentail tool to aid in assessment of variant significance.
Citation Format: Lisle E. Mose, David Marron, Joel S. Parker. Accurate detection of expressed variation in RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1678.
Abstract 169: Uncovering a myosin phosphatase regulator in pancreatic tumor cell mechanics and behavior
Authors: Angstadt Shantel M. 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) composes more than 80% of all pancreatic cancers and about 95% of exocrine pancreatic cancers. Patients typically present with symptoms post metastatic spread, which contributes to its overall lethality as the 3rd leading cause of cancer-related deaths with a median 5-year survival rate of about 8%. We are investigating the role of the myosin phosphatase targeting subunit 1 (MYPT1) in PDAC. MYPT1 serves as an interaction platform between a catalytic phosphatase subunit and the phosphorylated regulatory light chain (MLC) of myosin, allowing for MLC dephosphorylation and myosin inactivation. MYPT1 has been shown to elicit an antibody response in PDAC patients treated with a cytokine-secreting whole tumor cell vaccine. Additionally, MYPT1 has been shown to be upregulated in PDAC cells through immunohistological staining of surgically resected patient samples and in established PDAC cell lines. As a major regulator of non-muscle myosin II, MYPT1 has implications in cancer cell shape control, adhesion, and migration. To elucidate its implications, we are characterizing tumor cell phenotype with and without MYPT1 expression using the CRISPR genome editing system. We are assessing MYPT1’s effect on cell mechanics (e.g. cortical tension), if MYPT1 responds to applied mechanical stresses, and how MYPT1 affects each of the non-muscle myosin II paralogs’ ability to respond to these mechanical stresses. We are characterizing MYPT1’s impact on cell and tissue behavior, including cell growth, migratory, and invasive phenotypes in culture and in mouse models. Overall, our work will provide insight into MYPT1’s role in cancer cell behavior and response to its surrounding environment. The work will also provide insight for early investigations into MYPT1’s targetability and immunogenic role in PDAC immunotherapy.
Citation Format: Shantel M. Angstadt. Uncovering a myosin phosphatase regulator in pancreatic tumor cell mechanics and behavior [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 169.
Abstract 1704: Predicting survival and improving treatment for uterine serous carcinoma patients using USC78, a genomic risk score
Authors: Tran Lynn K. , Myers Emily K. , Mysona David P. , Tran Paul M. , Lee Wonsok , Wallbillich John J. , Kleven Daniel , Ghamande Sharad , She Jin-Xiong 
Published: August 2019

Abstract
Uterine serous carcinoma (USC) is a rare but particularly invasive histological subtype of uterine cancer, the most common gynecologic malignancy in developed countries. Though previous studies with small sample sizes have been conducted to identify transcriptomic and proteomic biomarkers for USC, none have resulted in a clinical assay for patient risk stratification. I have discovered a panel of 78 genes highly upregulated in poor prognosis patients from The Cancer Genome Atlas (TCGA) USC dataset. To create a composite score for our biomarker panel, I applied a machine learning algorithm (elastic net regression) to the TCGA USC gene expression data set to generate a model which outputs a linear predictor score (USC78) based on individual patients’ expression of the 78 genes from our signature. I then quantified gene expression from formalin-fixed paraffin embedded (FFPE) tumor tissue in our cohort of Augusta University (AU) patients and calculated their USC78 score to demonstrate the ability of this model to separate good and poor survival prognosis in a single-center, retrospective validation study. In both TCGA and AU, higher USC78 scores are associated with worse overall survival. This score is also able to risk stratify serous ovarian carcinoma patients in the TCGA data set, suggesting that USC78 may be an important prognosis prediction tool in serous gynecological cancers. Additionally, network analysis of these genes reveals increased TGF-B signaling correlates with the poor-prognosis USC78-high tumor expression profile. TGF-B inhibition has demonstrated chemosensitization effects in primary USC tumor cell lines. I aim to use USC78 to better understand the biological mechanisms behind poor survival prognosis in USC patients and identify potential therapeutic targets for USC. One such target is TGF-B inhibition, and further knockdown, overexpression, and inhibitor studies will be conducted to test whether TGF-B inhibition can improve USC patient prognosis.
Citation Format: Lynn K. Tran, Emily K. Myers, David P. Mysona, Paul M. Tran, Wonsok Lee, John J. Wallbillich, Daniel Kleven, Sharad Ghamande, Jin-Xiong She. Predicting survival and improving treatment for uterine serous carcinoma patients using USC78, a genomic risk score [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1704.
Abstract 1710: Role of Nurr1 in cervical cancer pathogenic pathway
Authors: Wan Kok Ting , Leung Thomas Ho Yin , Siu Michelle Kwan Yee , Ngan Hextan Yuen Sheung 
Published: August 2019

Abstract
Aims: To study the oncogenic role of Nurr1 in cervical cancer and elucidate the underlying mechanism.
Background: Orphan nuclear receptor related-1 protein (Nurr1) belonging to the NR4A family is important for carcinogenesis in multiple biological processes such as cell proliferation and apoptosis. It has been reported that the expression of Nurr1 is significantly correlated with various types of cancer, such as prostate and breast cancer. However, the significance of Nurr1 in cervical cancer etiology remains poorly understood.
Methods: Primary cancer cells were established from tumor tissues resected from cervical cancer patients. Six pairs of attached and spheroid cells derived from primary cervical cancer tissues were established namely CP-1A/CP-1S, CP-2A/CP-2S, CP-3A/CP-3S, CP-4A/CP-4S, CP-5A/CP-5S and CP-6A/CP-6S. A microarray was performed to identify differentially expressed genes in two pairs of attached and sphere cells, followed by validation with qPCR. Stable clones of cervical cancer cell lines with Nurr1 overexpression and knock-down were generated. The role of the selected gene was then functionally characterized by XTT assay, migration assay, spheroid formation assay, apoptosis assay, in vitro and in vivo tumorigenicity assay in cervical cancer cell lines. Downstream proteins of Nurr1 were detected by western blot.
Results: Microarray analysis showed that Nurr1 was highly expressed in sphere cells as compared with attached cells. Relative expression of Nurr1 mRNA in sphere cells was approximately 200-fold more than that in attached cells in qPCR validation. Cancer cell lines, in which Nurr1 was transiently knocked down by siRNA demonstrated an attenuation in proliferation rate, migration, spheroid formation and colony formation. By flow cytometric analysis, more cells were detected in early apoptotic stage with Nurr1 siRNA transfection as compared with NTC siRNA transfected cells, suggesting the role of Nurr1 in preventing cervical cancer cells from apoptosis. Western blotting also demonstrated that there was an increased expression of Bim and p21 in Nurr1 silenced cells. This may indicate the involvement of Nurr1 in modulating the transcription of pro-apoptotic and tumor suppressor genes.
Conclusion: Nurr1 is a potential oncogenic target in cervical cancer pathogenic pathway. Suppression of Nurr1 expression attenuated cancer progression and promoted apoptosis.
Citation Format: Kok Ting Wan, Thomas Ho Yin Leung, Michelle Kwan Yee Siu, Hextan Yuen Sheung Ngan. Role of Nurr1 in cervical cancer pathogenic pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1710.
Abstract 172: BCL11A regulation of extracellular matrix genes may be necessary for invasion of triple-negative breast cancer
Authors: Ingles Natasha N. , Seachrist Darcie , Keri Ruth 
Published: August 2019

Abstract
Triple-negative breast cancer (TNBC) represents 15% of all breast cancers, yet conveys the poorest patient prognoses due to the lack of targeted therapies and the high incidence of metastatic recurrence. This prompt recurrence is thought to be due, in part, to the high proportion of cancer stem cells (CSC) within TNBC tumors. Therefore, understanding what regulates CSCs and metastasis will allow us to significantly reduce cancer-related deaths. One of the transcription factors that is upregulated in TNBC is BCL11A, which is critical for CSC biology. We have found that BCL11A is necessary for TNBC invasion and metastasis. However, the genes that BCL11A targets to control invasion and metastasis are unknown. To identify the BCL11A-regulated transcriptome, we performed RNA-seq analysis of MDA-MD-231 TNBC cells transiently transfected with BCL11A-targeted siRNA or a non-silencing control. Gene set enrichment analysis of the differentially expressed genes revealed enrichment of genes involved in extracellular matrix and matrisome genes. Notably, BCL11A silencing reduced expression of several matrix-metalloproteases, with MMP1 being the most significantly differentially expressed gene. Thus, we hypothesize that BCL11A promotes TNBC invasiveness and metastasis through regulation of MMP expression. We confirmed downregulation of MMP1 and MMP9 mRNA and protein in response to BCL11A silencing by both qRT-PCR and western blot in independent MDA-MB-231 cells, as well as in the HCC1143 TNBC cell line. MMP activity was also reduced when assessed by fluorokine assay and gelatin zymography, for MMP1 and MMP9, respectively. Furthermore, both BCL11A and MMP expression is increased in brain-seeking clones of MDA-MB-231 cells and MMP1 and 9 expression is also reduced with BCL11A silencing. Together, these data suggest that BCL11A regulates TNBC invasion by reducing the expression of MMP1 and MMP9. Current studies are directly assessing the functional impact of MMP regulation by BCL11A on invasion and metastatic progression of TNBC.
Citation Format: Natasha N. Ingles, Darcie Seachrist, Ruth Keri. BCL11A regulation of extracellular matrix genes may be necessary for invasion of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 172.
Abstract 1730: DACH1 gene deletion extends portraits of human prostate cancer
Authors: Jiao Xuanmao , Sante Gabriele Di , Li Zhiping , Rocco Agnese Di , Wang Min , Ertel Adam , McCue Peter A. , South Andrew P. , Cordon-Cardo Carlos , Stokes Matthew P. , Marra Marco , Jones Steven J. , Kossenkov Andrew , Pestell Richard G. 
Published: August 2019

Abstract
Purpose of the study: This study was conducted to define the role of Dachshund in prostate cancer, through assessing human prostate cancer samples and through genetic deletion in the mouse. Prostate cancer (PCa), the second leading cause of death in American men, is a genetically heterogeneous disease, likely representing distinct genetic drivers, with terminal events caused primarily by metastasis. Substratification of PCa into genetic subtypes, forms the basis of rational therapy for PCa. A better molecular understanding of the disease is necessary in order to develop novel targeted therapies of metastatic PCa. Known genetic drivers to tumor initiation include PTEN and NKX3.1 deletions, rearrangements of the TMPRSS2 gene to the oncogenic ETS transcription factor, ERG, and genetic predisposing factors include germline DNA-repair gene mutations. The DACH1 gene, initially cloned as an inhibitor of Elipse, the hyperactive epidermal growth factor (EGFR) in Drosophila, was found to be reduced in abundance in several malignancies including breast and prostate cancer.
Results: In order to determine whether the DACH1 gene is deleted or mutated in prostate cancer we interrogated the genomic sequencing analysis of over 490 patients from 5 population cohorts. Homozygous deletion of DACH1 was identified in 18% (N=61), 11% (N=136), 10% (N=492), 7% (N=103) and 3% (N=150) of prostate cancer in 5 distinct cohorts. The prevalence of DACH1 gene deep deletions was higher in the metastasis than in the primary tumors. The Transgenic Adenocarcinoma Mouse Prostate (TRAMP) transgenic, Dach1fl/fl, and Probasin-Cre, ROSA26mT/mG transgenic mice were used to generate a prostate epithelial cell specific Dach1 gene knockout mouse (Probasin-Cre-Dach1fl/fl ROSA26mT/mG-TRAMP) lines. Prostate specific deletion of the murine Dach1 gene enhanced progression of prostatic intraepithelial neoplasia (PIN), associated with increased prostate epithelial cell proliferation, epithelial mesenchymal transition (EMT), DNA damage and inflammation.
Conclusions: DACH1 gene deletion may define a distinct subclass of prostate cancer that may benefit from PARP inhibitors, and platinum-based chemotherapy.
Citation Format: Xuanmao Jiao, Gabriele Di Sante, Zhiping Li, Agnese Di Rocco, Min Wang, Adam Ertel, Peter A. McCue, Andrew P. South, Carlos Cordon-Cardo, Matthew P. Stokes, Marco Marra, Steven J. Jones, Andrew Kossenkov, Richard G. Pestell. DACH1 gene deletion extends portraits of human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1730.
Abstract 1737: Association of inherited variants with chromosomal breaks in cancer
Authors: He Meng Xiao , Shahamatdar Sahar , Taylor-Weiner Amaro , Zack Travis , Ramachandran Sohini , Allen Eliezer Van 
Published: August 2019

Abstract
Background: Cancer cells frequently harbor genomic rearrangements and somatic copy number alterations that result from chromosome breaks, which vary in frequency across the genome. The distribution of breakpoint locations depends on features of the local genomic context, such as presence of certain retrotransposons. Moreover, inherited variants have been associated with specific chromosomal alterations in myeloproliferative neoplasms and in blood from cancer-free individuals. Here, we developed and applied computational methodology to broadly identify associations between inherited variants and the location of somatic breakpoints across cancers.
Methods: We analyzed TCGA Affymetrix Genome-Wide Human SNP Array 6.0 data from matched tumor-normal pairs (n = 5,923 samples remaining after quality control and selecting for individuals of predominantly European ancestry). Germline genotypes were called from normal samples using Birdseed v2. Allele-specific copy number analysis using both normal and tumor samples for each individual was performed using ASCAT v2.5.1. Breakpoints were inferred as the intervals between ASCAT-called somatic chromosomal segments.
We assigned individuals binary phenotypes corresponding to whether a somatic breakpoint was detected in non-overlapping 5 megabase bins of the genome. We then performed an association analysis between each phenotype and variants located on the same chromosome as the corresponding bin, adjusting for sex and ancestry via logistic regression with plink2. Analyses were performed separately for each disease type followed by a meta-analysis of association summary statistics with METAL.
Results and Conclusions: We identify several candidate associations between inherited variants and the presence of somatic breakpoints in specific regions of the genome (using a p-value cutoff of 5e-8 for each phenotype). Our results suggest that heritable genetic variation may be associated with risk of development of localized chromosome breaks in somatic cells. Ongoing work is aimed at validating the putative associations (for example using data from the PanCancer Analysis of Whole Genomes study) and identifying potential mechanisms associated with putative risk alleles.
Citation Format: Meng Xiao He, Sahar Shahamatdar, Amaro Taylor-Weiner, Travis Zack, Sohini Ramachandran, Eliezer Van Allen. Association of inherited variants with chromosomal breaks in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1737.