bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5361: Spatial genome organization as a framework for somatic alterations in human cancer
Authors: Akdemir Kadir C. , Futreal Andrew 
Published: August 2018

Abstract
Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Recent chromosome conformation studies have revealed that mammalian chromosomes are structured into tissue-invariant topologically associating domains (TADs) where the DNA within a given domain interacts more frequently together than with regions in other domains. Genes within the same TADs represent similar expression and histone-modification profiles. Therefore, regions separating different TADs (boundaries) have important roles in reinforcing the stability of these domain-wide features. Indeed, TAD boundary disruptions in human genetic disorders or human cancers lead to misregulation of certain genes, due to de novo enhancer exposure to promoters. Here, to understand effects and distributions of somatic structural variations across TADs, we utilized single nucleotide variations and genomic rearrangements from 2658 high-coverage whole genome sequencing data across various cancer types with paired normal samples. Our analysis revealed that deletions between repressed and active TADs result in up-regulation of genes on the repressed end of the deletions, whereas active domain genes remain unaffected. Interestingly, we further identified a strong correlation between the mutational distributions in human cancers and the spatial organization of the genome. Transcriptionally active TADs contain less mutation burden compared to inactive TADs, as a result regional mutation rates are drastically different around the boundaries delineating epigenetically distinct domains. However, mutation rates remain similar around the boundaries for samples with the DNA mismatch repair deficiency. Taken together, our analyses reveal new insights about genome architecture, aberrant gene expression and mutational distributions in human cancers.
Citation Format: Kadir C. Akdemir, Andrew Futreal. Spatial genome organization as a framework for somatic alterations in human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5361.
Abstract 5372: The mutational landscape of primary cutaneous melanoma
Authors: Chen Sofia Y. , Mamunur Rashid , Laye Jon , Bishop D. Timothy , Newton-Bishop Julia A. , Adams David J. 
Published: August 2018

Abstract
Large-scale melanoma genome profiling studies to date have mainly focused on metastatic tumors. To better understand the link between genomic changes and outcome, primary tumors must be studied.
We have designed a comprehensive targeted genomic panel to study genetic alterations in melanoma, and applied this to a large collection of 536 primary melanomas, part of the Leeds Melanoma Cohort. Patients were invited to participate 3 months after diagnosis of primary melanoma. 1% received targeted therapies or immunotherapy and thus, our analysis is reflective of the landscape of primary melanoma in the treatment naïve setting. The sequencing panel allowed us to study genetic alterations in over 500 genes, including more than 150 genes frequently mutated in melanoma and an additional 250 genes linked to other solid tumor types. Both tumor and germline DNA were analyzed for most samples.
The average somatic mutation rates we observed was 15 mutations/MB (0 to 236 mutations/MB), while the nonsynonymous mutational load ranged from 0 to 57 mutations/MB (average 4 mutations/MB). We found that a high mutational burden (highest 20%, &gt;45 nonsynonymous mutations/Mb) positively correlated with better survival (Cox proportional hazards model with age, sex and AJCC stage as additional covariates). Among the top recurrently mutated genes were well established melanoma driver genes such as BRAF (44%), NRAS (28%), NF1 (10%), CDKN2A (15%), TP53 (11%) and ARID2 (8%). We also found hotspot mutations in less well documented melanoma genes, including RQCD1 p.P131L (4.5%).
Altogether, our preliminary data shows a strong correlation between survival and high mutational load in primary melanomas. Our data also suggests a similar landscape of driver mutations in primary and metastatic melanoma, with some variants/genes possibly reflecting the differences in disease stage.
We will further investigate the mutational landscape in our cohort of primary melanomas, including analyses of gene co-occurrence and mutual exclusivity. Additionally, we will use extensive clinical parameters and transcriptomics to examine the possibility of predicting survival and other clinically relevant parameters in our cohort based on patient mutational profiles.
Citation Format: Sofia Y. Chen, Rashid Mamunur, Jon Laye, D. Timothy Bishop, Julia A. Newton-Bishop, David J. Adams. The mutational landscape of primary cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5372.
Abstract 5398: Companion diagnostic for predicting the efficacy of mTOR inhibitor in neuroendocrine tumor
Authors: Liu I-Hua , Chang Jia-Ming 
Published: August 2018

Abstract
Neuroendocrine tumor (NET) is having both characterizations of hormone and neurotransmitter secretion. The mTOR, a serine-threonine kinase inhibitor, was used for treating the NET tumors by affecting angiogeneic blood vascular vessels as a disrupting agent and killing the tumor cells by inhibiting the mTOR signalling. Everolimus is a U.S. FDA-approved drug for treating advanced breast cancer, which is investigated for use in NET treatment. The efficacy will be evaluated by exosome reflecting the tumor microenvironment secreted into blood circulation. NCI-H727 cells are a kind of NET tumor that show the secretion of chromogranin A (CgA) and serotonin. By profiling of exosome with miRNA, the efficacy may be predicted by the level of miRNA. Here, we demonstrated the pattern of miRNA profile in everolimus-treated NCI-H727 cells. MIR192 and MIR375 were consistently secreted in exosomes with a high level. A panel of miRNA, MIR24-2, MIR3131, and MIR708, was increased and showed a change greater than 0.5 fold compared with untreated cells. In conclusion, by analyzing the pattern of miRNA in exosomes, the efficacy of drug can be monitored during the treatment. A new therapeutic strategy can be tailored according to the miRNA pattern.
Citation Format: I-Hua Liu, Jia-Ming Chang. Companion diagnostic for predicting the efficacy of mTOR inhibitor in neuroendocrine tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5398.
Abstract 5400: A comprehensive analysis of the interactome of miR-21, an established oncomir, by Argonaute-CLIP analysis identifies novel conserved and species-specific targets of miR-21 in human liver and hepatocellular carcinoma
Authors: Koenig Aaron B. , Barajas Juan M. , Ghoshal Kalpana 
Published: August 2018

Abstract
MicroRNAs are ~22 nucleotide RNAs that regulate gene expression at the post-transcriptional level by binding messenger RNA transcripts. MicroRNA (miR)-21 participates in carcinogenesis in hepatocellular carcinoma (HCC) and other malignancies. Here we analyze the miR-21 interactome in HCC by high-throughput sequencing of RNA isolated by Argonaute cross-linking immunoprecipitation (Argonaute-CLIP) in nine HCC cases with matched livers. Argonaute-CLIP identified miR-21 bound to 580 target sites on coding transcripts, of which 332 were located in the coding sequences, 214 in the 3'-untranslated region, and 34 in the 5'-untranslated region, introns or downstream sequences. Overall, 403 target sites (69.5%) enriched for miR-21 in HCCs relative to liver. We compared expression of miR-21 targets in 377 patients with liver cancer registered in The Cancer Genome Atlas. Ago-CLIP miR-21 enrichment score in HCC distinguished expression of miR-21 targets by their correlation with miR-21 expression. Comparison of the miR-21 interactome in mouse and human livers identified common and species-specific targets. Among targets of miR-21, 27.6% were downregulated in HCC. The miR-21 interactome was predicted to regulate tumor metabolism by inhibiting PPAR alpha/RXR alpha and LXR/RXR signaling. To identify targets of miR-21, we matched Ago-CLIP targets to genes previously reported as aberrantly expressed after anti-miR-21 overexpression in HCC. RMND5A, encoding an E3 ubiquitin ligase, was identified as a potential target of miR-21 regulation and was variably expressed in HCC. Three predicted miR-21 targets, CAMSAP1, DDX1 and MARCKSL1, correlated with HCC patient survival. Collectively, our analysis biochemically identified novel targets of miR-21 likely to play a causal role in hepatocarcinogenesis.
Citation Format: Aaron B. Koenig, Juan M. Barajas, Kalpana Ghoshal. A comprehensive analysis of the interactome of miR-21, an established oncomir, by Argonaute-CLIP analysis identifies novel conserved and species-specific targets of miR-21 in human liver and hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5400.
Abstract 5403: Discovery of high metastatic potential microRNAs in human colorectal cancer
Authors: Lee Jee Hyun , Kim Gyeonghwa , Kim Hye Jin , Choi Gyu-Seog , Hur Keun 
Published: August 2018

Abstract
Background and Aim: Colorectal cancer (CRC) is the third most common cancer worldwide. More than half of the CRC patients have liver metastasis at the time of diagnosis, which is the major cause of cancer-related death in CRC. MicroRNAs (miRNAs) have been identified as modulators of the epithelial-mesenchymal transition (EMT)-mesenchymal to epithelial transition (MET) process by regulating transcription factors. However, it is not clear which specific miRNAs are critical drivers of CRC metastasis development. The aim of this study was to discovery novel high metastatic potential miRNAs in matched CRC and metastasis tissues, serum-exosome, and CRC cells with high metastasis property.
Materials and Methods: We isolated total RNAs from pairs of normal colon (NC), primary CRC (pCRC), liver metastasis (LM), normal liver (NL) tissue specimens, and pre-OP/post-OP serum-exosome sample from 15 each CRC patients. We also prepared total RNAs from 4 CRC cell lines (SW480, LS174T, COLO 205, and EMT-induced SW480) as well as exosome from their culture medium. To induce EMT process, epithelial phenotype CRC cell (SW480) was treated with epidermal growth factor (EGF). Next, miRNAs discovery step was conducted via NanoString analysis. Further miRNAs expression was determined by quantitative real-time PCR (qRT-PCR), and miRNAs expression was normalized relative to U6 and cel-miR-39 expression for tissue and serum-exosome samples, respectively.
Results: We successfully generated miRNAs expression profiles to distinguish NC vs. pCRC, pCRC vs. LM, LM vs. NL, and epithelial phenotype cells vs. high metastatic phenotype cells. Interestingly, a subset of miRNAs, including miRNA-100-5p, -339-3p, -549a, -1304-5p, and -1972, was commonly enhanced in LM, EMT-induced SW480, and high metastatic phenotype CRC cells compared to pCRC, SW480, and low metastatic phenotype CRC cells. In our further miRNAs validation analysis using pairs of pCRC and LM tissues from 15 CRC patients, miRNA-100-5p (P&lt;0.0001), miR-339-3p (P=0.0022), and miR-1972 (P&lt;0.0001) were significantly upregulated in pCRC than matched LM tissues. We also observed discordance expression patterns of miRNAs between CRC tissues and serum-exosome specimens.
Conclusions: Our findings suggest that a unique subset of miRNAs is involved in CRC metastasis development, which may associate with EMT process and acquiring of high metastatic potential in CRC cells. Moreover, our metastasis specific miRNAs profile might be useful for development of markers predicting and/or treatment of CRC patients with metastasis.
Citation Format: Jee Hyun Lee, Gyeonghwa Kim, Hye Jin Kim, Gyu-Seog Choi, Keun Hur. Discovery of high metastatic potential microRNAs in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5403.
Abstract 5412: miR155 and miR9 expression in human prostate cancer cell lines and prostate cancer tissue
Authors: Benedetti Ines , Rebollo Juan , Reyes Niradiz 
Published: August 2018

Abstract
Background: Differential expression of miRNAs between malignant, precancerous lesions, and nonmalignant prostate tissues may indicate that these molecules play a role in cancer biology. Several miRNAs have been commonly reported to be differentially expressed in prostate cancer, compared to benign prostate tissue, but some results have been contradictory. Expression patterns of specific miRNAs across prostate cancer, precancerous lesions, and benign tissue have not been determined.
Design: The expression patterns of 20 miRNAs were determined in the metastatic prostate cancer cells lines LNCaP and PC3, using the nontumorigenic prostate cell line PWR-1E as reference. Differentially expressed miR-9 and miR-155 were subsequently evaluated in epithelial cells obtained by laser capture microdissection from cancerous lesions, high-grade prostatic intraepithelial neoplasia, proliferative inflammatory atrophy, and benign tissue from radical prostatectomy and transurethral prostatectomy tissue specimens, from patients diagnosed with prostate cancer. Total RNA was extracted from the cell lines and microdissected epithelial cells and expression of miR-9 and miR-155 was evaluated by qPCR; miRNA levels in individual samples were normalized to corresponding RNU62 levels. Fold-change values were calculated, and p value &lt; 0.05 was considered statistically significant. The Ethical Review Board of the academic institution approved this study.
Results: Differential expression of several miRNAs was found between cell lines. Four miRNAs showed a similar expression profile in the cancer cell lines, two were overexpressed in metastatic cell lines LNCaP and PC3 compared to the nontumorigenic PWR-1E cells (hsa-miR-195, hsa-miR-9), and two were underexpressed (hsa-miR-143, hsa-miR-155). Evaluation of miRNA expression in laser capture microdissected epithelial cells showed a trend towards higher expression of miR-9, and lower expression of miR-155 in microdissected epithelial cells derived from prostate tissue with cancer and proliferative inflammatory atrophy compared to epithelial cells from benign tissue.
Conclusions: Our results are in agreement with the description of miR-9 as oncomiRNA. miR-155 was underexpressed in LNCaP and PC3 cells in relation to nontumorigenic PWR-1E cells. Also, this miRNA showed a trend towards underexpression in epithelial cells microdissected from prostate tissue with cancer and proliferative inflammatory atrophy compared to epithelial cells from benign tissue. Further studies of these deregulated miRNAs will help clarify their role in prostate tumorigenesis.
Citation Format: Ines Benedetti, Juan Rebollo, Niradiz Reyes. miR155 and miR9 expression in human prostate cancer cell lines and prostate cancer tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5412.
Abstract 5422: TMPRSS2-ERG fusions confers efficacy of enzalutamide in an in vivo bone tumor growth model
Authors: Chinni Sreenivasa R. , Semaan Louie , Cher Michael 
Published: August 2018

Abstract
Castrate Resistant Prostate Cancer (CRPC) is an advanced disease resistant to systemic anti-androgen therapies and resistance is primarily attributed to reactivation of AR through multiple mechanisms. TMPRSS2-ERG fusions have been shown to regulate AR signaling, interfere with pro-differentiation functions, and mediate oncogenic signaling. In fact, cooperation between AR and ERG drives invasive adenocarcinoma even in the castrate environment. We have recently shown that ERG regulates intra-tumoral androgen synthesis thereby facilitates AR function in CRPC disease. We hypothesize that enzalutamide treatment will be more effective in cells/tumors with TMPRSS2-ERG translocations because these tumors have increased AR signaling. In other words, AR blockade is likely to induce a greater treatment response in tumors with ERG gene fusions than in tumors without such fusions. ERG knockdown was performed with VCaP cells using lentiviral infections to generate VCaP ERGshRNA cells and control VCaP scr cells with scrambled shRNA. Cell-growth analysis was performed to determine the effect of enzalutamide. Luciferase tagged VCaP scr and shRNA infected cells were used in intra-tibial animal model for bone tumor growth analysis and enzalutamide treatment used to inhibit AR signaling in bone tumors. Reverse transcription, quantitative real-time PCR (RT-qPCR) was used to determine the expression of AR responsive genes and androgen biosynthetic enzyme genes; Western blotting (WB) samples, for ERG, AR and AKR1C3 in VCaP bone tumors. Enzalutamide inhibited VCaP scr more effectively than shERG cells. Analysis of AR responsive genes show that Enzalutamide treatment at 5 micro molar concentration inhibited 85-90% in VCaP Scr cells whereas these genes inhibited to lesser extent in VCaP shERG cells. In bone tumor growth experiment, VCaP ERG shRNA cells grown at slower than VCaP scr shRNA cells. Enzalutamide treatment resulted in a sever growth inhibition in VCaP scr shRNA cells compared to VCaP shERG cells. Androgen biosynthetic enzyme expression is lower VCaP shERG bone tumors compared to VCaP scr shRNA bone tumors and enzalutamide inhibited the enzyme expression in both types of tumors. These data suggest that ERG transcription factor regulates androgen biosynthetic enzyme expression and enzalutamide treatment is effective against VCaP bone tumors with an intact ERG expression, and knocking down ERG in VCaP cells leads lesser response for enzalutamide therapy.
Citation Format: Sreenivasa R. Chinni, Louie Semaan, Michael Cher. TMPRSS2-ERG fusions confers efficacy of enzalutamide in an in vivo bone tumor growth model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5422.
Abstract 5429: Targeting Nrf2 anti-oxidative pathway as a novel strategy to suppress IDH1-mutated cancer
Authors: Liu Yang 
Published: August 2018

Abstract
Background: Reactive oxygen species are recently recognized as a second messenger that affects many aspects in cell biology. In cancer cells, ROS has been proof closely related to metabolic reprogramming, tumor proliferation, progression and metastasis. In tumors with isocitrate dehydrogenase (IDH) mutations, the neomorphic enzyme results in unusual accumulation of ROS in cancer cells, suggesting distinctive vulnerabilities may be established in these types of cancer. However, the biologic function of ROS in IDH1-mutated cancers remains elusive.
Methods: In this study, we explored the ROS homeostasis in IDH1 mutated glioma. We investigated the correlation between ROS scavenging genes and overall survival in 530 IDH1-mutated glioma cases. Mechanistically, we focused on nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway and seek for novel therapeutic strategy by targeting ROS burden in cancer cells. We further investigated the therapeutic value of Nrf2 inhibitor, Brusatol, in IDH1 mutated cancer in vitro and in vivo.
Results: We found IDH1 mutation leads to substantial reprogramming in ROS homeostasis, highlighted with prompted ROS generation and detoxification. Stronger expression of ROS scavenging gene predicts drug resistance and poor disease outcome. Enhanced Nrf2-associated scavenging pathway was found essential to maintain reasonable intracellular ROS level during cancer progression. Targeting Nrf2 scavenging pathway not only led to ROS overload, DNA/protein oxidative damage, but also reduced tumor cell proliferation and xenograft growth in vivo.
Conclusions: IDH1 mutant glioma highly depend on Nrf2 scavenging pathway to maintain ROS homeostasis. Targeting ROS scavenging might be a novel approach to treat gliomas with IDH1 mutation.
Citation Format: Yang Liu. Targeting Nrf2 anti-oxidative pathway as a novel strategy to suppress IDH1-mutated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5429.
Abstract 5438: XPNPEP3: A novel transcriptional target of canonical Wnt/β-catenin signalling
Authors: Kumar Raju , Naz Ashmala , Kotapalli Viswakalyan , Gowrishankar Swarnalata , Rao Satish , Pollack Jonathan R. , Bashyam Murali Dharan 
Published: August 2018

Abstract
Canonical Wnt/β-catenin signalling plays pivotal roles during embryonic development and adult tissue regeneration. Its aberrant activation however drives expression of a panoply of genes to facilitate colorectal tumorigenesis. Hence, it is imperative to delineate the complete β-catenin transcriptome. We performed genome-wide mRNA profiling of sporadic rectal cancer samples stratified by Wnt status. Results revealed significant up-regulation of XPNPEP3 transcript levels along with that of canonical Wnt targets AXIN2 and EPHB2 in Wnt+ samples. The differential expression of XPNPEP3 was further validated by quantitative PCR (Q-PCR) in additional samples. Nuclear stabilization of β-catenin achieved through LiCl treatment in three colorectal cancer (CRC) cell lines followed by Q-PCR and promoter-luciferase assays confirmed up-regulation of XPNPEP3. XPNPEP3 encodes X-prolyl aminopeptidase 3 which functions to remove the penultimate N-terminal Proline residue from nascent proteins and appears to play a role in ciliary function. Immunohistochemistry based expression analysis using a CRC tissue microarray revealed significant correlation between XPNPEP3 levels and β-catenin nuclear localization as well as increased XPNPEP3 expression in tumor compared to matched normal samples. Survival analysis of The Cancer Genome Atlas (TCGA) breast invasive carcinoma, skin cutaneous melanoma and lung adenocarcinoma data sets revealed poor survival among patients having perturbed XPNPEP3 expression. Characterization of possible oncogenic function of XPNPEP3 in CRC cells and in mice tumor xenografts is currently underway. Altogether, our results suggest XPNPEP3 to be a novel transcriptional target of Wnt/β-catenin signalling having a possible significance in CRC tumorigenesis.
Citation Format: Raju Kumar, Ashmala Naz, Viswakalyan Kotapalli, Swarnalata Gowrishankar, Satish Rao, Jonathan R. Pollack, Murali Dharan Bashyam. XPNPEP3: A novel transcriptional target of canonical Wnt/β-catenin signalling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5438.