tbuckley/cabot-search huggingface dataset:
Abstract 3186: Taxane resistance in prostate cancer: A role for miRNA 181a
Authors: Cameron M. Armstrong, Chengfei Liu, Wei Lou, Allen C. Gao
Journal: Cancer Research (2017)

Abstract Introduction: Docetaxel (DTX) is one of the primary drugs used for treating castration resistant prostate cancer (CRPC). Unfortunately, over time patients invariably develop resistance to DTX therapy and their disease will continue to progress. The mechanisms by which resistance develops are still incompletely understood. This study seeks to determine the involvement of miRNAs, specifically miR-181a, in DTX resistance in CRPC. Methods: Total RNA from parental C4-2B prostate cancer cells and DTX resistant C4-2B cells (C4-2B TaxR) was submitted for small RNA deep sequencing. Data was analyzed to ascertain which miRNAs expressions were most altered in C4-2B TaxR cells compared to parental cells. Having identified an increase in miR-181a in resistant cells, its expression was modulated in C4-2B and C4-2B TaxR cells by transfecting them with miR-181a mimics or antisense, respectively. Following transfection, cell number was determined after 48 h with or without DTX. Cross resistance to cabazitaxel induced by miR-181a was also determined. Western blots were used to determine ABCB1 protein expression and rhodamine assays used to assess activity. Phospho-p53 expression was assessed by western blot and apoptosis was measured by ELISA in C4-2B TaxR cells with inhibited miR-181a expression with or without DTX. Results: miR-181a is significantly upregulated in C4-2B TaxR cells compared to parental C4-2B cells as analyzed by small RNA sequencing. Overexpression of miR-181a in C4-2B cells confers DTX and cabazitaxel resistance. Knockdown of miR-181a in C4-2B TaxR cells re-sensitizes them to treatment with both DTX and cabazitaxel. miR-181a knockdown alone induced apoptosis in C4-2B TaxR cells which is further enhanced by DTX. We next assessed if miR-181a altered expression or activity of ABCB1, which is overexpressed/active in C4-2B TaxR cells and promotes resistance to DTX by pumping the drug out of cells. We found that miR-181a does not impact ABCB1 expression or activity. Since we previously demonstrated that phospho-p53 can modulate DTX sensitivity, we determined if miR-181a can alter p53 expression in C4-2B TaxR cells. Knockdown of miR-181a in C4-2B TaxR cells induced phospho-p53 expression, suggesting that miR-181a induced resistance to DTX is mediated by inhibition of phospho-p53 expression. Conclusions: Overexpression of miR-181a in C4-2B TaxR cells contributes to their resistance to DTX and inhibition of miR-181a expression can restore treatment response. This is due, in part, to modulation of p53 phosphorylation and induction of apoptosis. Note: This abstract was not presented at the meeting. Citation Format: Cameron M. Armstrong, Chengfei Liu, Wei Lou, Allen C. Gao. Taxane resistance in prostate cancer: A role for miRNA 181a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3186. doi:10.1158/1538-7445.AM2017-3186
Identification of novel prostate cancer drivers using RegNetDriver: a framework for integration of genetic and epigenetic alterations with tissue-specific regulatory network
Authors: Priyanka Dhingra, Alexander Martinez-Fundichely, Adeline Berger, Franklin W. Huang, Andre Neil Forbes, Eric Minwei Liu, Deli Liu, Andrea Sboner, Pablo Tamayo, David S. Rickman, Mark A. Rubin, Ekta Khurana
Journal: Genome biology (2017)

We report a novel computational method, RegNetDriver, to identify tumorigenic drivers using the combined effects of coding and non-coding single nucleotide variants, structural variants, and DNA methylation changes in the DNase I hypersensitivity based regulatory network. Integration of multi-omics data from 521 prostate tumor samples indicated a stronger regulatory impact of structural variants, as they affect more transcription factor hubs in the tissue-specific network. Moreover, crosstalk between transcription factor hub expression modulated by structural variants and methylation levels likely leads to the differential expression of target genes. We report known prostate tumor regulatory drivers and nominate novel transcription factors (ERF, CREB3L1, and POU2F2), which are supported by functional validation.
Abstract 286: Forecast of the incidence and etiology of liver cancer in Taiwan, Japan, United States, and United Kingdom: toward harmonization of East and West
Authors: Emily Han-Chung H. Hsiue, Wei-Cheng Lo, Hsien-Ho Lin, Chih-Hung Hsu, Ann-Lii Cheng
Journal: Cancer Research (2017)

Abstract Background The global epidemiology of primary liver cancer (PLC), primarily hepatocellular carcinoma (HCC), has evolved significantly in the past decades because of improved control of viral hepatitis and the growing prevalence of metabolic factors. We conducted a quantitative forecast of the incidence and etiology of PLC. Methods Incidence rates of PLC were projected in two endemic Asian countries (Taiwan and Japan) and two Western countries (the United States and United Kingdom) with rigorous cancer registry. The annual incidence of PLC (ICD-10 C22.0) between 1980 and 2013 were obtained from the Taiwan Cancer Registry Database, the Japan National Cancer Center, the US SEER 9 database, Cancer Research UK, and the European Network of Cancer Registry. Incidence rates were projected to year 2035 by an age-period-cohort model with a power link function. The population attributable fractions (PAF) of chronic hepatitis B (HBV), chronic hepatitis C (HCV), alcohol consumption, obesity, and diabetes mellitus (DM) for HCC in Taiwan were projected to 2045. The prevalence of each risk factor was obtained from national surveys and projected inferentially by using a log-linear model or simple linear assumption. The relative risk of each factor was derived from pooled literature data. Results From 2013 to 2035, incidence rates of PLC in Taiwan are estimated to decrease by more than 50% in both men (49.3 to 24.2/100,000) and women (19.7 to 9.2/100,000). In Japan, incidence rates have plateaued in the 1990s, and are expected to continue to decline to 17.0/100,000 for men and 6.3/100,000 for women. Conversely, rates in the UK are projected to increase by more than 30% in both men (13.5 to 18.2/100,000) and women (6.0 to 8.1/100,000). A more modest increase is expected in the US, from 10.2 to 12.5/100,000 for men and 3.3 to 3.5/100,000 for women. In Taiwan, the PAF of HBV, the predominant risk factor of HCC, is predicted to decrease from 54.3% in 2015 to 34.4% in 2045. By 2045, the PAFs of obesity and DM are estimated to reach 11.9% and 15.4%, respectively, the latter similar to that of HCV (15.0%). Conclusion PLC incidence rates are forecast to follow a trend of convergence in four representative countries. Metabolic factors are expected to play increasingly important etiologic role in HCC even in regions currently endemic for viral hepatitis. Citation Format: Emily Han-Chung H. Hsiue, Wei-Cheng Lo, Hsien-Ho Lin, Chih-Hung Hsu, Ann-Lii Cheng. Forecast of the incidence and etiology of liver cancer in Taiwan, Japan, United States, and United Kingdom: toward harmonization of East and West [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 286. doi:10.1158/1538-7445.AM2017-286
Abstract 1287: Multigene panel testing and risk estimates in 10,233 ovarian cancer cases
Authors: Jenna Lilyquist, Holly LaDuca, Eric Polley, Hermela Shimelis, Chunling Hu, Raymond Moore, Steven N. Hart, Fergus J. Couch, Jill Dolinsky, David E. Goldgar
Journal: Cancer Research (2017)

Abstract Germline pathogenic variants in BRCA1 and BRCA2 account for 10% of ovarian cancer (OC), including ovarian, fallopian tube, and primary peritoneal carcinomas. Pathogenic variants in BRIP1, RAD51C, RAD51D, and other cancer predisposition genes have been observed in another 2% to 5% of OCs. However, the specific genes associated with OC and estimates of risk associated with pathogenic variants in the individual genes are not well defined. We sought to determine the relevance of multigene panel testing results for OC cases. The study was focused on 140,449 individuals, including 10,233 OC cases, receiving clinical panel testing of cancer predisposition genes. Standardized relative risks (SRR) for pathogenic variants in 18 cancer predisposition genes were estimated using reference controls from the Exome Aggregation Consortium (ExAC). The median (range) age at diagnosis of OC was 57 (21-90) years. OC cases were 76.2% Caucasian, 3.6% African American, 4.6% Asian, 4.7% Hispanic, and 10.9% unknown/other. Among the 10,233 OC cases, 1391 (13.6%) had pathogenic mutations, including 1032 pathogenic mutations among the 7793 Caucasian OC cases (13.2%). Using the non-Finnish European ExAC (excluding TCGA samples) reference controls, the allele frequency for all pathogenic variants in each gene was summed and compared to the frequency of mutations in the Caucasian OC cases. Pathogenic variants in the known OC predisposition genes: BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, and RAD51D were associated with a high risk of OC (SRR&amp;gt;4.0). Additionally, significant associations were observed for pathogenic variants in suspected OC risk genes ATM and PALB2 (SRR=2.06 and 2.78, respectively). This study identified several genes routinely screened on multigene panel testing that confer high or moderate risks of OC. Associations with known OC predisposition genes were confirmed. In addition, this study provides evidence that PALB2 is a moderate risk OC gene, and that ATM may confer lower to moderate risks of OC. If confirmed in future studies, these risks should be carefully considered in future screening and management of OC patients. In contrast, BARD1 and genes in the MRN complex were not associated with clinically relevant risks of OC. Citation Format: Jenna Lilyquist, Holly LaDuca, Eric Polley, Hermela Shimelis, Chunling Hu, Raymond Moore, Steven N. Hart, Fergus J. Couch, Jill Dolinsky, David E. Goldgar. Multigene panel testing and risk estimates in 10,233 ovarian cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1287. doi:10.1158/1538-7445.AM2017-1287
Abstract LB-280: The landscape of somatic microsatellite indels across cancer: detection and identification of driver events
Authors: Yosef E. Maruvka, Kent W. Mouw, Rosa Karlic, Rasanna Parasuraman, Atanas Kamburov, Paz Polak, Nicholas J. Haradhvala, Julian M. Hess, Esther Rheinbay, Yehuda Brody, Lior Z. Braunstein, Alan D’Andrea, Michael S. Lawrence, Adam Bass, Andre Bernards, Franziska Michor, Gad Getz
Journal: Cancer Research (2017)

Abstract Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that are abundant in the human genome and exhibit high rates of mutations in the form of insertions or deletions of the repeated motif (MS indels). Despite their prevalence, the contribution of somatic MS indels to cancer is largely unexplored due to difficulties in detecting them and assessing their significance. Here, we present a comprehensive analysis of MS indels across 20 tumor types. We characterize the overall MS indel landscape and detect genes with candidate driver MS indel events. We present two novel tools: MSMuTect for accurate detection of somatic MS indels and MSMutSig for identifying candidate cancer genes containing events at higher frequency than expected by chance. We observe high variability of the frequency of MS indels across tumors and demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite stable (MSS) tumors from tumors with microsatellite instability (MSI). Applying MSMutSig across 6,788 tumors from 20 different tumor types identified 7 genes with significant MS indel hotspots: ACVR2A, RNF43, DOCK3, MSH3, ESRP1, PRDM2 and JAK1. In the four genes that have been previously implicated in cancer (ACVR2A, RNF43, JAK1 and MSH3), we identified previously unreported MS indels events. Three of the genes with significant loci - DOCK3, PRDM2 and ESRP1- had not been previously listed as cancer genes. MS indels in DOCK3, a negative regulator of the WNT pathway, were mutually exclusive with mutations in CTNNB1. MS indels in ESRP1, an RNA processing gene, correlated with alternative splicing of FGFR2, an event associated with the epithelial-to-mesenchymal transition. Overall, our comprehensive analysis of somatic MS indels across cancer highlights their importance, particularly in MSI tumors, significantly contributes to the ongoing global efforts to detect cancer genes, and may improve classification of patients into clinically-relevant subgroups. Citation Format: Yosef E. Maruvka, Kent W. Mouw, Rosa Karlic, Rasanna Parasuraman, Atanas Kamburov, Paz Polak, Nicholas J. Haradhvala, Julian M. Hess, Esther Rheinbay, Yehuda Brody, Lior Z. Braunstein, Alan D’Andrea, Michael S. Lawrence, Adam Bass, Andre Bernards, Franziska Michor, Gad Getz. The landscape of somatic microsatellite indels across cancer: detection and identification of driver events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-280. doi:10.1158/1538-7445.AM2017-LB-280
Abstract 3845: Establishment and characterization of patient-derived xenografts of clear cell carcinoma of the ovary
Authors: Hidemichi Watari, Daisuke Endo, Kouhei Honda, Mihoko Kunitomo, Toshiyuki Nomura, Noriaki Sakuragi
Journal: Cancer Research (2017)

Abstract Background; The patient-derived xenograft (PDX) model is likely to reflect original human cancer biology compared to cultured cell lines, since tumor tissues are directly implanted into animals. PDX models of ovarian cancer have been developed, but were not fully characterized at the molecular level, especially for clear cell carcinoma (CCC), which is more prevalent in Japan than western countries, exhibits chemoresistant phenotype and poor survival. The development of new treatment strategies and the better understanding of biology of CCC both depend on clinically relevant animal models. In particular, molecular annotated PDX models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. Methods; We transplanted 19 parent (primary or metastatic) tumors directly into NOG mice. The histologic characteristics were compared between parental tumors and PDX ones. Among CCC pairs, gene expression analysis, gene mutation analysis were conducted on parental tumors and corresponding PDX tumors. Response to chemotherapeutic agents was analyzed using PDX tumors of CCC, and correlated with clinical outcome. Results; Six of nineteen (31.6%) transplanted tumors could be passaged. Gene expression profiles revealed that engrafted tumors expressed more proliferation-related genes than those of non-englafted ones. Among six PDX models established, two were found to be CCC. Two PDX tumors of CCC maintained the histologic characteristics of parental CCC tumors. Gene expression profile revealed similar results between primary CCC and PDX tumors of CCC except that PDXs lost expression of immune-related genes.. Gene mutational analysis showed similar pattern between primary CCC and PDX of CCC. Drug-sensitivity test showed resistance to carboplatin in two PDX tumors of CCC, which is consistent with their clinical outcomes. Conclusions. PDXs of CCC were established and found to retain histologic and clinical features of original tumors, and can be utilized to screen new target drugs for platinum-resistant CCC. Citation Format: Hidemichi Watari, Daisuke Endo, Kouhei Honda, Mihoko Kunitomo, Toshiyuki Nomura, Noriaki Sakuragi. Establishment and characterization of patient-derived xenografts of clear cell carcinoma of the ovary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3845. doi:10.1158/1538-7445.AM2017-3845
Abstract 1814: IL11 mediates tumor resistance to anti-VEGF therapy in lung cancer
Authors: Jie Li, Kun Xie, Shenglin Mei, Yuanjian Xu, Hua Gu, Dong Li, Kaiming Chen, Fei Tao, Jiya Eerdeng, Jianmin Fang
Journal: Cancer Research (2017)

Abstract Anti-angiogenic therapy has been used for the treatment of a number of solid tumors in clinic, however, survival benefit is often limited due to development of tumor resistance to the therapy. In previous studies, we developed a mouse Lewis lung carcinoma (LLC) tumor model that is resistant to anti-VEGF therapy. In this model, we identified that Interleukin 11 (IL11) was among the most significantly upregulated genes in the resistant tumors. In current study, we demonstrated that IL11 was a pro-angiogenic factor and played a key role in the development of resistance to anti-VEGF therapy in LLC tumor. IL11 could effectively induce HUVEC proliferation, migration and capillary tube formation in vitro. It enhanced expression of MMP9 in endothelial cells. The conditioned medium from the resistant LLC cell culture could induce HUVEC migration, even VEGF was blocked, and this effect was attenuated by recombinant IL11 decoy receptor, an IL-11 inhibitor. Furthermore, combination therapy of anti-VEGF agent and IL11 blockade exhibited enhanced anti-tumor activity in lung cancer model. In addition, based on bioinformatics analysis on over 500 RNA-seq data deposited to The Cancer Genome Atlas (TCGA), we found that IL11 was highly expressed in various tumor types in patients. Data showed that high IL11 can predict a poor outcome in the lung cancer. The patients with the lower IL11 expression have significantly longer median survival time than those with higher expression. These findings support a role of IL11 signal as a compensatory angiogenic pathway that might trigger tumor resistance to anti-VEGF treatment. Therapeutically targeting IL11 could have a value in overcoming tumor resistance to anti-VEGF therapy. Citation Format: Jie Li, Kun Xie, Shenglin Mei, Yuanjian Xu, Hua Gu, Dong Li, Kaiming Chen, Fei Tao, Jiya Eerdeng, Jianmin Fang. IL11 mediates tumor resistance to anti-VEGF therapy in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1814. doi:10.1158/1538-7445.AM2017-1814
Abstract 2849: Identification of active enhancers as potential biomarkers of aggressive colorectal cancer
Authors: Zhiquan Wang
Journal: Cancer Research (2017)

Abstract Colorectal cancer is the third most common cancer and second leading cause of cancer-related deaths in the United States. Tumor metastasis is the primary cause of mortality. Even with aggressive surgical and therapeutic management approaches, more than one third of patients will develop metastatic disease. Understanding the molecular changes that drive tumor cells to the metastatic state is key to developing targeted therapies and identifying early-stage markers for progression. To identify changes that promote cell invasiveness, a hallmark of tumor progression, we exposed the pre-metastatic SW-480 colorectal cancer cell line to multiple rounds of selection for the capacity to invade through a synthetic extra-cellular matrix. Following repeated selection, invasiveness increased by more than 10-fold. Epithelial markers, such as E-cadherin, were repressed and markers commonly associated with tumor cells that have undergone epithelial-mesenchymal transition, such as N-cadherin and Vimentin, were upregulated. Likewise, invasive cells showed increased affinity for ECM components. Paired ChIP-seq and RNA-seq revealed likely roles for epigenetic alterations in driving gene expression changes. Furthermore, the epigenetic changes followed ordered patterns of activation and inactivation, suggesting that these epigenetic signatures may provide insight into early mechanisms associated with epithelial-mesenchymal transition. Collectively, our data suggest that early epigenetic markers may be better early predictors of colorectal cancer aggressiveness than gene expression patterns and support the use of this in vitro metastasis model to study the molecular mechanisms of cancer progression. Citation Format: Zhiquan Wang. Identification of active enhancers as potential biomarkers of aggressive colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2849. doi:10.1158/1538-7445.AM2017-2849
Production of Malignancy in Vitro. VIII. Observations on the Mitochondria and Golgi Material
Authors: Albert J. Dalton, Wilton R. Earle, Edward L. Schilling, Virginia B. Peters, Emma Shelton
Journal: JNCI Journal of the National Cancer Institute (1944)

Production of Malignancy in Vitro. VIII. Observations on the Mitochondria and Golgi Material Get access Albert J. Dalton, Albert J. Dalton cytologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Wilton R. Earle, Wilton R. Earle senior cytologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Edward L. Schilling, Edward L. Schilling technical assistance National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Virginia B. Peters, Virginia B. Peters National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Emma Shelton Emma Shelton National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 4, Issue 6, June 1944, Pages 539–554, https://doi.org/10.1093/jnci/4.6.539 Published: 01 June 1944
Next-Generation Sequencing of Endobronchial Ultrasound Transbronchial Needle Aspiration Specimens in Lung Cancer
Authors: David Fielding, Andrew J. Dalley, Farzad Bashirzadeh, Mahendra Singh, Lakshmy Nandakumar, Amy E. McCart Reed, Debra Black, Stephen Kazakoff, Katia Nones, John Pearson, Nic Waddell, Sunil R. Lakhani, Peter T. Simpson
Journal: American Journal of Respiratory and Critical Care Medicine (2017)