bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2480: MutSpliceDB: A database of splice sites mutations effects
Authors: Palmisano Alida , Vural Suleyman , Zhao Yingdong , Sonkin Dmitriy 
Published: August 2019

Abstract
Splice site mutations are one of the well-known classes of genetic alterations playing an important role in biology. Splice site mutations in cancer are most frequently observed as inactivating alterations in tumor suppressor genes (for example, TP53 or RB1) and to a lesser degree as activating alterations in oncogenes (for example MET). Splice site mutations may lead to alterations in mRNA transcripts, causing for example exon(s) inclusion/exclusion or, intron retention. Interpreting the consequences of a specific splice site mutation is not straightforward, especially if the mutation is located outside of the canonical splice sites. Accurate interpretation of the impact a splice site mutation has can further our understanding of biology, influence patient treatment, and in case of germline splice site mutations, may also have relevance to familial disease predisposition. To facilitate the interpretation of splice site mutation effects, we developed MutSpliceDB: https://brb.nci.nih.gov/splicing a public resource of splice sites mutations effects, documenting mutation effect(s) on splicing based on manually reviewed RNA-seq BAM files from sample(s) with particular splice site mutations.
Citation Format: Alida Palmisano, Suleyman Vural, Yingdong Zhao, Dmitriy Sonkin. MutSpliceDB: A database of splice sites mutations effects [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 2480.
Abstract 2488: CellMinerCDB and CellMiner web-applications for genomics and pharmacogenomics analyses of cancer cell lines
Authors: Reinhold William C. , Varma Sudir , Wang Yang-Hsin , Elloumi Fathi , Pommier Yves 
Published: August 2019

Abstract
The CellMiner (http://discover.nci.nih.gov/cellminer)and CellMinerCDB (https://discover.nci.nih.gov/cellminercdb/) web-applications provide complimentary functionality and datatsets that may be used for comparisons of genomic, molecular and pharmacological data within the NCI-60 cancerous cell lines, Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC), Cancer Therapeutics Response Portal (CTRP), NCI/DTP small cell lung cancer (SCLC), and NCI Almanac cell line sets. CellMiner contains data for the NCI-60, including the most extensive sets of molecular and drug activity data (generated by the NCI Developmental Therapeutics Program https://dtp.cancer.gov),found for any of the databases. CellMinerCDB contains all the above mentioned cell line sets, including the substantially increased cell line numbers and tissue of origin types found in the CCLE, GDSC, and CTRP. The two web-applications have separate but complimentary functionalities. Each cell line set has some variable number of data types, some of which measure the same parameters, and some that do not. The number and make up of cell lines also varies, from 60 for the NCI-60, 69 for the SCLC, and ~1000 for the CCLE, GDSC, and CTRP. As there are partial overlaps of cell lines between many of these cell line sets, one may fill in some data type gaps by merging data from two sources, as well as do quality control by comparisons of the same data from multiple institutions. This rich set of data and functions facilitates the exploration of the relationships between and among molecular alterations and pharmacological responses in cancer cell lines from the omic perspective.
Citation Format: William C. Reinhold, Sudir Varma, Yang-Hsin Wang, Fathi Elloumi, Yves Pommier. CellMinerCDB and CellMiner web-applications for genomics and pharmacogenomics analyses of cancer cell lines [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 2488.
Abstract 249: Combination of ONC201 with radiation exhibits synergistic efficacy in high grade gliomas and other advanced cancers
Authors: Tarapore Rohinton S. , Jhawar Sachin , Stein Mark , Zloza Andrew , Mueller Sabine , Zhang Jie , Amoroso Francesca , Mills Ian , Oster Wolfgang , Allen Joshua 
Published: August 2019

Abstract
Background: Radiation is widely administered in many treatment settings for solid tumors. ONC201 is the first small molecule DRD2 antagonist for oncology that is being investigated in advanced cancer clinical trials as a single agent. ONC201 has exhibited preclinical and clinical anti-tumor activity in high grade gliomas and its immunostimulatory activity involving natural killer (NK) cells has been recently reported. Given that ONC201 exhibits broad synergy with anti-cancer drugs, excellent safety, and single activity in tumor types where radiation is used routinely, we evaluated the combination of ONC201 with radiation.
Methods: Cell viability was evaluated in human and/or mouse breast, prostate and high grade glioma cell lines in response to ONC201 (1 - 10uM), radiation (2- 10 Gy), or the combination. Incubation times ranged from 24 to 96 hours and the sequence of the two agents in combination was varied.
Results: Cell viability assays for ONC201 in combination with radiation in breast or prostate cancer cell lines revealed a cytotoxic response to the combination that was superior to either single agent. Western blot analysis of PC3 cells showed a synergistic induction of CHOP and ATF6 that are components of the integrated stress response. In glioblastoma or diffuse intrinsic pontine glioma (DIPG) cell lines, combination indices computed from cell viability experiments indicated modest synergy (~0.7 CI) for the combination ranging between 1-5 µM ONC201 and 2-10 Gy. In MDA-MB-468 breast cancer cells, Western blot analysis demonstrated a striking induction of PARP cleavage, a marker of caspase-mediated apoptosis, with 2 µM ONC201 in combination with 2 Gy radiation, whereas either single agent produced minimal PARP cleavage. In 4T1 murine triple-negative breast cancer subcutaneous tumors, the combination of oral ONC201 and radiation produced antitumor effects at subtherapeutic doses that required CD4+ T cells and NK cells.
Conclusions: ONC201 combined with radiation produced additive or synergistic anti-cancer effects in high grade glioma, breast and prostate cancer in vitro and increased anti-tumor efficacy in an in vivo model of breast cancer that involved immune cells.
Citation Format: Rohinton S. Tarapore, Sachin Jhawar, Mark Stein, Andrew Zloza, Sabine Mueller, Jie Zhang, Francesca Amoroso, Ian Mills, Wolfgang Oster, Joshua Allen. Combination of ONC201 with radiation exhibits synergistic efficacy in high grade gliomas and other advanced cancers [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 249.
Abstract 2494: Emodin inhibits colon cancer by altering BCL-2 family proteins and cell survival pathways
Authors: Saunders Ian T. , Kapur Neeraj , Mir Hina , Singh Shailesh 
Published: August 2019

Abstract
The therapeutic outcome of colon cancer (CoCa) is often compromised due to the development of chemoresistance and toxicities associated with current therapeutics. Hence, identification of less toxic and efficacious agent is needed to treat CoCa. In this study, we tested the effect of natural agent, Emodin (6-methyl-1,3,8-trihydroxyanthraquinone) isolated from Asian plant rhubarb, on CoCa cell death and survival. Effects of Emodin on CoCa (DLD-1 and COLO-201) cell viability and death was determined by MTT and Annexin-V assays, respectively. Apoptosis-specific protein antibody array was used to define the Emodin induced molecular mechanisms involved in cell death vs. survival and results were confirmed by western blot analysis. Mitochondrial membrane potential and the expression/localization of Bcl-2 family protein were assessed via flow cytometry and WB, respectively. Our data show Emodin decreased the viability of CoCa cells and induced apoptotic cell death in a time and dose-dependent manner. Emodin-induced apoptosis resulted in increased death receptor expression, modulated caspase activation, and an imbalance in the Bax/Bcl-2 ratio. Changes in Bcl-2 family protein expression and localization correlated with loss in mitochondrial membrane potential. Emodin also negatively impacted MAPK/JNK, PI3K/AKT, NF-kB and STAT signaling pathways, which are associated with cell growth, differentiation, and Bcl-2 family expression or function. Modulation of cell survival and apoptotic pathways by Emodin and specifically the impact on Bcl-2 projects Emodin significance as promising therapeutic agent for CoCa treatment.
Citation Format: Ian T. Saunders, Neeraj Kapur, Hina Mir, Shailesh Singh. Emodin inhibits colon cancer by altering BCL-2 family proteins and cell survival pathways [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 2494.
Abstract 2507: Genetic alterations affecting treatment response in locally advanced breast cancers
Authors: Venizelos Andreas , Knappskog Stian , Loees Inger Marie , Eikesdal Hans Petter , Lønning Per Eystein 
Published: August 2019

Abstract
Resistance to chemotherapy remains a main cause of death among cancer patients. The primary aim of the present study was to identify genetic alterations predicting resistance to chemotherapy by whole exome sequencing (WES) of tumors subject to neoadjuvant sequential treatment with epirubicin and docetaxel. A long term goal is to identify biomarkers that may be applicable in testing for drug sensitivity prior to commencement of therapy for individual patients, leading to early administration of optimal treatment and sparing patients from side-effects of inefficient treatment. From a total of 100 patients treated with sequential monotherapy in the neoadjuvant setting, we performed WES on 146 tumor samples and matching blood samples from 51 patients. Biopsies for research were taken before treatment start, at the time of treatment switch and at the time of surgery. In the present work, we have analysed WES data to assess the mutational- and the copy number landscape and compared these results between patients having a good or poor response to the two administered drugs. SNV analysis revealed imbalance in several well established breast cancer related genes, between the different response groups. Copy number assessments revealed a general increase in copy number gains in chromosome 16 and increase of copy number losses in chromosomes 1 and X after treatment with epirubicin, indicating that subclones harbouring different types of CNVs are selected for during treatment. Correspondingly, after treatment with docetaxel we found a general increase of copy number gains in chromosome 8 and an increase of copy number losses in chromosomes 1 and 8. Finally, we assessed overall mutational signatures and observed shifts in these profiles during the two treatments.
Citation Format: Andreas Venizelos, Stian Knappskog, Inger Marie Loees, Hans Petter Eikesdal, Per Eystein Lønning. Genetic alterations affecting treatment response in locally advanced breast cancers [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 2507.
Abstract 2508: Genomic alterations of BRCA1/2 genes in Chinese solid tumor patients
Authors: Wang Junjian , Liu Lingxiang , Ni Bin , Chen Xiaoqian , Li Ling , Shi Junping , Chen Jierong , Yao Ming 
Published: August 2019

Abstract
Background: BRCA1 and BRCA2 are tumor suppressor genes that play an important role in DNA repair pathways. Germline mutations in BRCA1 and BRCA2 contribute to a significant number of familial and hereditary breast and/or ovarian cancers. Additionally, BRCA 1/2 alterations induce sensitivity to poly ADP ribose polymerase inhibitors (PARPi). Therefore, the detection of BRCA 1/2 mutations in solid tumor patients is essential to predict the sensitivity to PARPi therapy.
Methods: FFPE tumor and matched blood samples of 5269 Chinese patients with solid tumor were collected for next generation sequencing (NGS) based assay. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements and fusions in selected genes were assessed.
Results: Three hundred patients with BRCA1/2 mutations were identified in 5269 Chinese patients with solid tumor. The patients included 177 males and 123 females with a median age of 58. Highest yields of BRCA1/2 mutations were found in patients with ovarian (24.5%) and breast (12.3%) cancers. BRCA1/2 mutations were also identified in gastric cancer (8.9%), cholangiocarcinoma (8.8%), colorectal cancer (7.1%), esophageal cancer (6.1%), gallbladder cancer (5.1%), lung cancer (4.7%), soft tissue tumor (4.1%) and pancreatic cancer (4.0%). SNVs and short Indels (84.9%) were the most common variant types of BRCA1/2, while the percentages of gene rearrangements and fusions, CNV and long Indels were 12.0%, 1.6% and 1.5%, respectively. Among patients with BRCA1/2 mutations, 224 (74.7%) patients harbored somatic mutations, 73 (24.3%) patients harbored germline mutations, 3 (1.0%) patients harbored both somatic and germline mutations. Interestingly, all of the variant types of germline mutations were SNVs and short Indels. The mutation sites were distributed in the full length of BRCA1/2 genes. No hot spot mutation was observed.
Conclusions: Our data revealed that BRCA1/2 mutations occurred in 5.7% of Chinese patients with solid tumor. NGS targeted sequencing provides comprehensive and accurate information of BRCA1/2 mutations. Beyond ovarian and breast cancers, BRCA1/2 mutations could be detected in other solid tumors, which suggests potential clinical benefits from PARPi therapy.
Citation Format: Junjian Wang, Lingxiang Liu, Bin Ni, Xiaoqian Chen, Ling Li, Junping Shi, Jierong Chen, Ming Yao. Genomic alterations of BRCA1/2 genes in Chinese solid tumor patients [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 2508.
Abstract 2524: Hallmarks of kinase fusions in Chinese tumors
Authors: Shi Lin , Ce Limuge , Wang Yanyan , Zhou Zisong , Ma Jing , Dong Hua , Ye Yizhou , Sun Shuyang 
Published: August 2019

Abstract
Kinase fusions are essential drivers to tumor genesis and generally response well to kinase inhibitors. Kinase fusion protein often represent ideal targets and many fusion genes have been well established as therapeutic targets as well as biomarkers, such as BCR-ABL fusion in CML and ALK fusion in lung cancer. In a CAP certified lab 3DMed we describe here a pan-cancer analysis of 8599 patient samples from assayed with comprehensive genomic profiling. Tissue samples were sequencing with a lab validated Masterview gene panel with intronic baiting for 30 fusion genes. Plasma samples were sequencing with a lab validated CGP150 gene panel with intronic baiting for 16 fusion genes. The kinase fusions genes we analyzed are included in both gene panels. Fusions were detected by a sensitive, breakpoint based method and the results were confirmed by manual inspection of the soft-clipped reads. Tumor mutational burden (TMB) was determined by coding region SNV and indel variant counts per Mb for tumor tissue sample only. We collect evidence for all possible gene fusion alterations in all the qualified samples and then focused on the analysis of kinase fusions in lung tissue samples. We surveyed gene fusions across 20 solid tumor types. 196/8599 (2.3%) samples harbored kinase fusion. 31.7% samples are from lung cancer patients and 74% of the 196 kinase fusions are found in lung cancer samples. The average of TMB score in kinase fusion positive samples was 5.17 vs. 11.35 (Wilcox test, P &lt; 0.001) for lung cancer cases. 13% of the kinase fusions positive lung cancer samples co-occur with a known driver mutation such as EGFR or ALK mutation. TMB score in subgroup with kinase fusion (with or without another oncogene driver mutation) is significantly lower than that of subgroup without fusion (Wilcox test, P &lt; 0.01). TMB scores in the kinase fusion positive patients is significantly lower than the fusion negative patients, which suggests that the kinase fusion positive subgroup may not response well to the immune checkpoint inhibitor. There are unmet clinical needs for more fusion kinase inhibitors with the increasing detection sensitivity for kinase fusions by NGS. Our finding have immediate clinical implications for cancer diagnosis and expand the therapeutic options for cancer patients’ care, as approved or exploratory drugs exist for many of these kinases.
Citation Format: Lin Shi, Limuge Ce, Yanyan Wang, Zisong Zhou, Jing Ma, Hua Dong, Yizhou Ye, Shuyang Sun. Hallmarks of kinase fusions in Chinese tumors [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 2524.
Abstract 2540: Mitotic Golgi vesiculation enables human papillomavirus to evade cGAS/STING
Authors: Forte Brittany L. , Bratton Shauna M. , Campos Samuel K. 
Published: August 2019

Abstract
Oncogenic human papillomaviruses (HPVs) infect and replicate in differentiating mucosal epithelium, causing 5% of cancers worldwide and essentially all cervical cancers. During infection, HPV must traffic viral genome (vDNA) to the nuclei of basal keratinocytes. Minor capsid protein L2 facilitates intracellular transport of vDNA to the Golgi; upon mitosis, the L2-vDNA complex penetrates limiting membranes and localizes to mitotic chromosomes, ensuring infection of both daughter cells.
Cytosolic DNA sensor cGAS recognizes cytosolic dsDNA and produces second messenger cGAMP; cGAMP causes activation and relocalization of ER-resident STING to the Golgi, where it recruits TBK1 to phosphorylate and activate IRF3, initiating a type-I IFN response. The cGAS/STING pathway is assumed, though never demonstrated, to be inactive during mitosis to avoid detecting self-DNA. Since the Golgi is a platform for STING/TBK1/IRF3 recruitment and activation, we hypothesize natural Golgi dispersal deactivates cGAS/STING during mitosis. Further, we hypothesize HPV has evolved to traffic to and translocate from the mitotic Golgi as an immunoevasive tactic to avoid detection by cGAS/STING during mitosis.
HaCaTs, a human keratinocyte line, were transfected with DNA or infected with HPV pseudovirions and analyzed for cGAS/STING activation. DNA transfection resulted in IRF3 phosphorylation and nuclear translocation, and STING translocation to the Golgi, indicating cGAS/STING activity. Strikingly, chemical disruption of the Golgi ribbon potently blocked IRF3 activation in response to foreign DNA, suggesting Golgi morphology might modulate cGAS/STING activity during mitosis. In accordance, DNA-dependent IRF3 phosphorylation was transiently reduced in synchronized mitotic cells, but chemical impairment of mitotic Golgi vesiculation enabled cGAS/STING activation, even without foreign DNA transfection. Further, HPV infection resulted in minimal IRF3 phosphorylation, indicating HPV can efficiently evade detection during initial infection.
To determine if HPV’s unique trafficking enables evasion, we used cationic liposomes to permit premature virion translocation across limiting membranes. Such treatment renders a non-infectious, translocation-defective mutant HPV infectious, yet susceptible to cGAS/STING sensing. Overall, the cGAS/STING pathway may be inactivated by mitotic Golgi dispersal, allowing HPV to evade detection during mitosis.
Citation Format: Brittany L. Forte, Shauna M. Bratton, Samuel K. Campos. Mitotic Golgi vesiculation enables human papillomavirus to evade cGAS/STING [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 2540.
Abstract 2556: Enhanced expression of human cyclin G1 (CCNG1) gene in metastatic cancer, a novel biomarker in development for CCNG1 inhibitor therapy
Authors: Gordon Erlinda M. , Szeto Christopher , Ravicz Joshua R. , Reddy Sandeep , Morse Michael , Chawla Sant , Hall Frederick 
Published: August 2019

Abstract
Background: Metastatic cancer is associated with, hitherto, an invariably fatal outcome. DeltaRex-G, a CCNG1 inhibitor, has induced long term (9-12 year-) survivorship in patients with metastatic melanoma, sarcoma, lymphoma and cancer of pancreas and breast.
Purpose: To evaluate CCNG1 expression in tumors as a novel biomarker for identification of patients who are likely to benefit from CCNG1 inhibitor therapy.
Methods: RNA sequence analysis was used to compare CCNG1 expression in tumor (TCGA, N=9161) versus normal tissues (TGCA, N=678 and GTEx, N=7187) from 20 organ sites, and in primary vs metastatic melanoma (N=106 & 367 respectively). Using IHC staining, the significance of differences between the number of CCNG1+ and Ki-67+ cells in normal tissues vs tumors were evaluated using paired Student’s t test. Pearson’s coefficient of correlation was used to evaluate the relationship between the number of Ki-67+ vs CCNG1+ cells.
Results: CCNG1 gene expression, by RNA sequence analysis, was significantly enhanced in melanoma, sarcoma, leukemia, and cancers of the lung, thyroid, brain, liver, prostate, testicle, head and neck, bladder, kidney, adrenal, cervix, and pancreas, compared to normal tissues (p = 0.006- 1.8E-58), and even greater, in metastatic vs primary melanoma. In a subset of melanoma tumors, there was overall positive correlation with progression/metastasis in both Ki67 and CCNG1 expression levels. Consistent with these findings, IHC showed significant differences when comparing CCNG1 nuclear staining percentages between analogous healthy and cancerous tissues (p = 0.002, df = 11). The nuclear staining percentages of CCNG1 and Ki-67 share a statistically significant, positive correlation (r = .936977, p &lt; 0.00001). Further, in some patients, the level of CCNG1 expression by IHC fluctuated over time.
Conclusion: Taken together, these data indicate that (1) CCNG1 expression, is frequently enhanced in cancerous tumors compared to their normal analogous counterparts, and (2) the level of CCNG1 expression may change over time, necessitating real time analysis in order to determine the optimal timing for CCNG1 inhibitor therapy. A Phase 2 basket study of DeltaRex-G cell cycle checkpoint inhibitor therapy is planned to correlate treatment outcome parameters with CCNG1 expression in patients’ tumors and circulating tumor cells.
Citation Format: Erlinda M. Gordon, Christopher Szeto, Joshua R. Ravicz, Sandeep Reddy, Michael Morse, Sant Chawla, Frederick Hall. Enhanced expression of human cyclin G1 (CCNG1) gene in metastatic cancer, a novel biomarker in development for CCNG1 inhibitor therapy [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 2556.