bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4194: Rare cancer’s ‘valley of death’: Critical gaps in data, research, and funding
Authors: Treuting Robert L. , Murphy Sean , Murphy Niall , Rao Bovey , Goyal Anekha , Tuccillo Nico , Kim Ryan Ki-Hoon , Parker Dylan , Arline Katherine 
Published: August 2019

Abstract
Over 370 forms of rare cancer compose at least 29.7% of all U.S. cancer diagnoses, or over 500,000 Americans per year. And yet, available data, research, and public funding related to these indications is insufficient in comparison with the 20 forms of non-rare cancers. Rare cancer is defined by the American Cancer Society as a cancer having an incidence of &lt;6 per 100,000 per year. A review of the AACR Annual Proceedings 2018 showed that at least 150 rare cancers were not the focus of any abstract. Non-rare forms of breast cancer, expected to represent 11.9% of new cancer cases in 2018, had almost the same coverage (1081 abstracts, 25.6%) as all rare cancers combined (1155 abstracts, 27.3%). Rare cancers which were included in AACR 2018 were the focus of an average of 5 abstracts each, while the 20 non-rare cancers were the focus of an average of 154 each. That gap in basic science is also visible in broader data sources. A computational review of the 10,000 most recent cancer-related publications in PubMed showed that over 100 rare cancers had no publications, while that was true of only 1 non-rare cancer. Included rare cancers had an average of 3.2 mentions in PubMed abstracts, while non-rare cancers had an average of 115. Adequate patient-derived tumor gene expression data is critical for targeted drug development. Analysis of the Gene Expression Omnibus (GEO) repository demonstrated that, while all 20 non-rare cancers had DataSets, over 100 rare cancers had none. On average, each rare cancer included in GEO had 1.04 DataSets, while each non-rare cancer had 22.8. Government grants to companies are an important tool for bridging the drug development “valley of death” between basic science and the clinic. Between 2013 and 2017, 781 SBIRs and STTRs related to cancer research, development, or treatment were identified. 489 of them related to a specific cancer or cancers. Of those grants, 41.5% were related to breast, lung, or prostate cancers. 22.3% were related to rare cancers. Among rare cancers, glioblastoma was the specific focus of the most grants (18). 356 forms of rare cancer were not the specific focus of any grant. Pediatric cancers, which are all rare, were the focus of 8 grants (1%). These data highlight a significant gap in rare cancer-focused data, research, and public funding which contributes to lower availability of clinical trials and therapeutics for over half a million U.S. patients per year.
Citation Format: Robert L. Treuting, Sean Murphy, Niall Murphy, Bovey Rao, Anekha Goyal, Nico Tuccillo, Ryan Ki-Hoon Kim, Dylan Parker, Katherine Arline. Rare cancer’s ‘valley of death’: Critical gaps in data, research, and funding [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 4194.
Abstract 4227: Salvage genetic testing on buccal swab samples using liquid in situ amplification identifies genetic mutations from previous test failures
Authors: Weiss Glen J. , Ford Andrew , Brown Charmaine , Caver Elizabeth , Vallejo Matthew , Adeyemi Claribel , Collins Forrest , Yeh Chen-Hsiung 
Published: August 2019

Abstract
Background: NCCN guidelines version 2.2019 address BRCA1/2 testing for men with a personal history of prostate cancer limited to Gleason ≥7 and specific family history features. Inherited genetic mutations have been identified in up to 12% of metastatic prostate cancer, primarily in DNA repair genes. Here we report liquid in situ amplification (LISA) technique followed by hereditary testing on buccal swab samples that had previously failed to yield a genetic testing result.
Methods: Previously failed buccal swab samples from another CLIA-certified laboratory were re-prepared using LISA. Qubit quantification following LISA revealed goodDNA concentrations even for these poor-quality swab samples ranging from 5 to 70 ng/uL, which is sufficient for next-generation sequencing analysis (NGS). Coding regions of ATM, BRCA1, BRCA2, CHEK2, PALB2, and RAD51D genes were amplified by a panel of specific primer pools followed by massively parallel sequencing for the identification of germline mutations. Minimal sequencing coverage was set as 50X, and pathogenic, likely pathogenic, and variants of unknown significance (VUS) were classified and reported.
Results: Buccal swab samples from 29 men with at least intermediate-risk prostate cancer were received as low-yield, low-quality DNA (n=12), pre-cut swabs in preservation solution (n=6), and aged swab samples (n=11). LISA and subsequent NGS testing was able to salvage results for 24/29 (82.8%) (failed samples included 4 aged swab and 1 pre-cut swab). 1 patient had a pathogenic BRCA1 mutation (c.4309delT) and 3 patients had VUS (BRCA1 c.4776C&gt;G, BRCA1 c.1846_1848delTCT, and RAD51D c.268G&gt;A). The remaining 20/29 (69.0%) samples have either benign or likely benign variants.
Conclusions: LISA applied to these previously failed samples was able to salvage results for over 80% of cases, including the identification of a pathogenic BRCA1 mutation which led cascade hereditary testing for immediate family members. It also provided confirmation for nearly 70% of cases about the absence of hereditary risk for the genes on the panel.
Citation Format: Glen J. Weiss, Andrew Ford, Charmaine Brown, Elizabeth Caver, Matthew Vallejo, Claribel Adeyemi, Forrest Collins, Chen-Hsiung Yeh. Salvage genetic testing on buccal swab samples using liquid in situ amplification identifies genetic mutations from previous test failures [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 4227.
Abstract 4231: Association between age of first full-term pregnancy and subsequent breast cancer risk
Authors: Tabassum Neha 
Published: August 2019

Abstract
Introduction
Amongst the various risk factors for breast cancer (BC), age at first full-term pregnancy is still a complex problem. Early first full-term pregnancy (before 25 years of age) is believed to confer protection towards the development of BC after menopause compared to the risk in nulliparous women but is also correlated with a transient increase in the risk of developing BC soon after pregnancy. On the other hand, a late first pregnancy (after 35 years of age) is believed to increase the risk of developing breast cancer after menopause, equating or increasing the risk compared to nulliparous women.
Material and Methods
In our project, currently, we aim to do a pilot study with 4 fresh frozen normal samples of nulliparous and early-and late-parous women from Komen tissue bank (USA) and to create a mathematical model to determine how rates of both drivers and passengers mutations are affected by pregnancy and how the risk can be determined in parous and nulliparous women. We plan to measure low-frequency mutations from fresh frozen normal breast samples from patients with different reproductive stages using both Whole Genome Sequencing in this pilot group,and later on to expand the findings with Exome Sequencing on the remaining cohort of 55 normal samples.
Results and Discussions
We are currently in the process of analysing the data from the whole genome sequencing and whilst we do this, we are also collecting DNA from laser-capture microdissected epithelial and stromal cells, for the remaining samples. Bioinformatics tools are used to eliminate germline mutations from the stroma and to determine where the mutations are located within the genome, and how their frequency changes within the sample cohort.
Conclusion
While this study is aimed to understand the scientific basis of breast cancer and therefore it is not clinically applicable in the immediate future, understanding the cancer risk associated with age of pregnancy will provide future patients, in particular from at-risk categories, with an informed choice when deciding to plan a pregnancy and a surveillance programme could also be implemented to closely monitor any changes in the breast after a late pregnancy and improve early detection. Furthermore, we could hypothesise that in the long-term future, with the wider application of mammary ductoscopy, breast samples could be analysed in the clinic to calculate the mutation rate of the patient and identify individual risk. This risk stratification along with available predictors such as the ‘Gail model’ could be applied in breast cancer surveillance programmes.
Note: This abstract was not presented at the meeting.
Citation Format: Neha Tabassum. Association between age of first full-term pregnancy and subsequent breast cancer risk [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 4231.
Abstract 4237: CC chemokines are differentially expressed in breast cancer and are associated with racial disparity
Authors: Thomas Jeronay K. , Mir Hina , Kapur Neeraj , Singh Shailesh 
Published: August 2019

Abstract
Despite recent advances in diagnosis and treatment Breast cancer (BrCa) still impacts women’s lives and this impact is disproportional in African Americans (AA) compared to European Americans (EA). Addressing socioeconomic and behavioral status has not reduced the race-specific gap in BrCa outcome, suggesting contribution of biological differences in BrCa disparity. We have previously shown involvement of chemokines in the pathogenesis of BrCa. In this study, we have determined the expression of CC chemokines in BrCa tissues and normal tissues utilizing the ONCOMINE database. Further, we determined clinical parameters associated with the CC chemokines overexpressed in BrCa tissues using The Cancer Genome Atlas (TCGA). Additionally, using Bc-GenExMiner and KMplotter we determined the effects of CC chemokines on reoccurrence, overall and relapse-free survival. Our analysis shows overexpression of CCL5, CCL7, CCL11, CCL17, CCL20, CCL22 and CCL25 mRNA in BrCa tissues compared to normal. Overexpression of CCL21 and CCL22 were significantly correlated with metastatic recurrence. High mRNA levels of CCL7, CCL8, CCL17, CCL20 and CCL25 predicted a decrease in overall survival and CCL7 and CCL8 expression showed a trend in decreased relapse-free survival. Furthermore, overexpression of CCL17 and CCL25 was associated with decreased overall survival in AA whereas in EA, CCL8 was associated with a decrease in overall survival. Interestingly, expression of CCL5, CCL8, CCL17, CCL20 and CCL25 were highest in TNBC tissues. Expression of CCL11 and CCL22 were associated with HER2. In addition to these, there was an association with CC chemokines expression with age in BrCa. Higher CCL11 expression was noted in younger women and CCL8, CCL20, CCL22 and CCL25 expression was higher in older women. Furthermore, CCL25 was significantly elevated and CCL8 was nearly significant in AA tissues when compared to EA. Expression of CCL7, CCL8, and CCL25 were associated with stage. In conclusion, our analysis suggests an association of CC chemokines in BrCa progression, overall survival and observed disparity in disease outcome between AA and EA patients.
Citation Format: Jeronay K. Thomas, Hina Mir, Neeraj Kapur, Shailesh Singh. CC chemokines are differentially expressed in breast cancer and are associated with racial disparity [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 4237.
Abstract 4246: Association of transcriptional levels of folate-mediated one-carbon metabolism related genes in cancer cell lines with drug treatment response
Authors: Krushkal Julia , Vural Suleyman , Min Dong-Joon 
Published: August 2019

Abstract
Folate-mediated one-carbon metabolism (OCM) is essential for growth and survival of cancer cells. It affects biosynthesis of nucleotides and amino acids, regulation of redox status, methylation of nucleic acids and proteins, and genome maintenance. We investigated whether the response of cancer cells to antitumor therapy treatment may be partially influenced by variation in expression of one-carbon metabolism genes. We used publicly available gene expression data and drug response measures for 251 antitumor agents in 635 cancer cell lines with matching information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources. We examined whether pre-treatment expression levels of OCM-related genes were associated with drug response. Among the 34 OCM genes examined, expression of GART, TYMS, SHMT2, MTR, ALDH2, BHMT, MAT2B, MTHFD2, NNMT, and SLC46A1 showed modest correlations with response to treatment with a variety of antitumor agents. Higher expression levels of the SLC46A1 transporter gene were associated with resistance to multiple drugs, whereas elevated expression of GART, TYMS, SHMT2, MTR, BHMT, and MAT2B was associated with chemosensitivity to multiple antitumor agents. NNMT expression was bimodally distributed and showed different directions of association with various agents. Correlation of increased NNMT expression with sensitivity to dasatinib was validated in the NCI-60 cancer cell line panel. Expression of several OCM genes was strongly associated with expression of multiple components of drug target pathways. For example, expression of both TYMS and GART was strongly positively correlated with BRCA1 expression, NNMT expression was associated with expression of multiple drug target genes including EGFR and ABL2, and the expression of TYMS, DHFR, and SHMT1 was positively correlated with AURKB expression. Pretreatment expression levels of many OCM genes including DHFR, TYMS, ATIC, GART, AHCY, MTHFD1, SLC19A1, and multiple other genes were positively correlated with each other, suggesting their co-regulation. In contrast, NNMT expression was negatively correlated with expression of several other OCM genes. Further studies could investigate whether correlations of expression levels of individual OCM genes with drug response are related to specific metabolic roles of these genes or whether such associations may be due to the general increase in cellular growth and proliferation and tumor progression, which may affect sensitivity to cancer treatment.
Citation Format: Julia Krushkal, Suleyman Vural, Dong-Joon Min. Association of transcriptional levels of folate-mediated one-carbon metabolism related genes in cancer cell lines with drug treatment response [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 4246.
Abstract 4254: Integrated analysis with MVisAGe identifies concordant and discordant genomic alterations of driver genes
Authors: Walter Vonn , Du Ying , Danilova Ludmila , Hayward Michele , Hayes D. Neil 
Published: August 2019

Abstract
Integrated analyses of multiple genomic datatypes are now common in cancer profiling studies. Such data present opportunities for numerous computational experiments, yet analytic pipelines are limited. Tools such as the cBioPortal and Regulome Explorer, while useful, are not easy to access programmatically or implement locally. The MVisAGe R package allows users to quantify gene-level associations between two genomic datatypes in order to investigate the effect of genomic alterations (e.g. DNA copy number changes on gene expression). Visualizing Pearson/Spearman correlation coefficients according to the genomic positions of the underlying genes provides a powerful yet novel tool for conducting exploratory analyses. We demonstrate its utility by analyzing three publicly available datasets from squamous tumors. Our approach highlights canonical oncogenes in chr11q13 that displayed the strongest associations between expression and copy number, including CCND1 and CTTN, genes not identified by copy number analysis in the primary reports. We demonstrate highly concordant usage of shared oncogenes on chr3q, yet strikingly diverse oncogene usage on chr11q as a function of HPV infection status. Regions of chr19 that display remarkable associations between methylation and gene expression were identified, as were previously unreported miRNA-gene expression associations that may contribute to the epithelial-to-mesenchymal transition.
Citation Format: Vonn Walter, Ying Du, Ludmila Danilova, Michele Hayward, D. Neil Hayes. Integrated analysis with MVisAGe identifies concordant and discordant genomic alterations of driver genes [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 4254.
Abstract 4260: Novel insights into immunotherapy by deep mining of big cancer genomic data
Authors: Liang Han 
Published: August 2019

Abstract
Immunotherapy has revolutionized patient care and cancer research. To gain novel insights into immunotherapy, we performed the pan-cancer analyses of &gt;11,000 tumor samples of 33 cancer types from The Cancer Genome Atlas and CPTAC as well as large amounts of in-house immunotherapy related data. Through the mining on these large-scale cancer genomics and proteomics data, I will discuss three novel ideas that would challenge the current paradigm for developing effective immunotherapy. (I) Checkpoint inhibition: antibody is NOT the only approach. I will discuss the role of enhancers in regulating immune checkpoint. (II) Neoantigen: Somatic mutations are NOT the only source. I will discuss the contribution of RNA editing to proteomics diversity and neoantigen in cancer. (III) Predictive markers: gene-based markers is NOT the only option. I will discuss the utility of a global energy index for predicting the response to anti-PD1 treatment. Collectively, these results suggest novel directions for future immunotherapy development.
Citation Format: Han Liang. Novel insights into immunotherapy by deep mining of big cancer genomic data [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 4260.
Abstract 4265: Transient versus permanent autophagy inhibition in pancreatic ductal adenocarcinoma
Authors: Pearce Jane B. , O'Flanagan Ciara H. , Hursting Stephen D. 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, with a 5- year survival rate of less than 5 percent. KRAS-driven PDACs often exhibit increased dependence on autophagy, a process by which cells degrade internal components to mobilize energy stores. When faced with cellular stress, such as nutrient deprivation, tumor growth may initially slow in response to decreasing supplies of growth factors and cytokines. Under these conditions, the induction of autophagy can enable continued tumor growth even in the presence of nutrient stress. Therefore, we posited that nutrient restriction in combination with autophagy inhibition would synergistically disrupt aberrant metabolic pathways and more effectively stunt PDAC tumor progression.
To determine the impact of transient autophagy inhibition, cells were treated with 10 μM of the pharmaceutical agent chloroquine (CQ) for 48 hours. To modulate growth factor/cytokine signaling as well as nutrient sensing signaling serum and glucose restriction were used in vitro. Next, permanent autophagy ablation was achieved through CRISPR/Cas9 technology, autophagy related 5 (Atg5) was deleted in Panc02 cells generating an autophagy-deficient (Atg-/-) PDAC cell line. Growth kinetics were determined in a range of culture matrixes to determine the proliferation rate, invasiveness, and anchorage independence of cells.
The combination of CQ and nutrient stress elicited an additive effect on cellular proliferation in both murine and human-derived KRAS mutant PDAC cells (Panc02 and MIA PaCa-2 respectively). In contrast, Atg5-/- Panc02 cells did not display any alteration in cellular proliferation in vitro. Atg5 deletion resulted in decreased expression of mesenchymal markers N-Cadherin and Snail as well as decreased invasiveness and anchorage independent colony formation. Upon intrapancreatic injection in a syngeneic model, Atg-/- cells exhibited reduced tumor growth relative to control Atg5+/+cells, indicating the compensatory mechanisms effective in vitro failed to protect these cells in vivo. Thus, our findings reveal a potential synergism between autophagy inhibition and nutrient stress in PDAC.
Citation Format: Jane B. Pearce, Ciara H. O'Flanagan, Stephen D. Hursting. Transient versus permanent autophagy inhibition in pancreatic ductal adenocarcinoma [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 4265.
Abstract 4267: mTORC1-dependent tumors have innate vulnerability to autophagic cell death by HDAC inhibitors
Authors: Yang Fuchun , Wang Chenran , Sun Shaogang , Haas Michael , Yeo Syn , Guan Jun-Lin 
Published: August 2019

Abstract
mTORC1 plays a significant role in the development and progression of many different types of cancers. Although mTORC1 inhibitors, such as Rapamycin, have anti-tumor effects on some specific cancers, their efficacy is still largely limited to anti-proliferative effects. Histone deacetylase (HDAC) inhibitors have been proven to be effective in cancer treatment including some solid cancers. We have previously established a vascular tumor cell line, Tsc1Δ EC, which was derived from Tsc1 deletion in mouse endothelial cells leading to constitutive activation of mTORC1. Here, we found that a pan-HDAC inhibitor, SAHA, caused Tsc1Δ EC cell death and growth arrest in vitro and in vivo. Our data showed that a selective Class I HDAC inhibitor CI994 treatment also caused Tsc1Δ EC cell death. Unlike mTORC1 inhibitors, the anti-tumor activity of SAHA was dependent on mTORC1 activation but it had little effect on mTORC1 activity in mTORC1 activated tumor cells. We found that Z-VAD-FMK, a pan-caspase inhibitor, had no inhibitory effect on SAHA treatment. Cell death pathway array analysis revealed that SAHA treatment in Tsc1ΔEC upregulated autophagy-related genes. Further experiments revealed that both autophagy gene Fip200 deletion and autophagy inhibition by spautin-1 in Tsc1Δ EC impaired tumor cell death by SAHA treatment. We further found that SAHA could play a role by increasing reactive oxygen species (ROS) via autophagy. Fip200 deletion caused Nrf2 activation through p62 accumulation, which can lead to antioxidation effect through p62-Keap1-Nrf2 pathway. We showed that inhibition of p62 expression re-sensitized Fip200 deleted Tsc1Δ EC to SAHA treatment. Taken together, HDAC inhibitors treatment provides an alternative promising therapeutic strategy for mTORC1-dependent cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Fuchun Yang, Chenran Wang, Shaogang Sun, Michael Haas, Syn Yeo, Jun-Lin Guan. mTORC1-dependent tumors have innate vulnerability to autophagic cell death by HDAC inhibitors [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 4267.