bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 334: Detection of BRCAness by a functional biomarker
Authors: Lee Chih-Ying , Ko Min-Yu , Lei Kai-Hang , Chi Peter 
Published: August 2018

Abstract
Homologous recombination (HR) is an error-free repair pathway to eliminate DNA double-strand breaks and cells with deficiency of HR repair are highly sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, targeting HR-defective cells becomes a new therapeutic approach for cancer patients. HR deficiency can be identified as BRCAness which may be due to mutations or epigenetic silencing in genes involved in HR, such as BRCA1 and BRCA2. Recent studies have developed several approaches to analyze HR status of cancer cells including RAD51 focus formation assay, large-scale mutational signatures analysis, and genome-wide transcriptome profiling. However, these assays provide an indirect estimation of HR status. We wish to directly measure HR rate in cancer cells. We have successfully developed two approaches, plasmid-based and virus-based functional assays, to directly quantify HR activity in cells and serve as a functional biomarker. Our results show that the signal of the functional biomarker specifically depends on the presence of the key enzyme, RAD51 recombinase, in HR. Finally, these functional assays can be utilized in different cancer cell types to determine the HR activity and can be a functional biomarker to evaluate the “BRCAness” status for the treatment of PARP inhibitors.
Citation Format: Chih-Ying Lee, Min-Yu Ko, Kai-Hang Lei, Peter Chi. Detection of BRCAness by a functional biomarker [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 334.
Abstract 3355: Clock genes DEC1 and BMAL1 regulate the expression of stem cell marker genes Sox2 and c-Myc in cervical cancer
Authors: Sato Fuyuki , Muragaki Yasueru 
Published: August 2018

Abstract
It has been reported that abnormalities of clock genes are associated with tumor progression. Clock genes CLOCK, BMAL1/2, Differentiated embryonic chondrocyte gene (DEC)1/2, PER1/2/3 and CRY1/2 play important roles in the regulation of cell proliferation, cell cycle, apoptosis, epithelial to mesenchymal transition (EMT) and metastasis. We have shown that DEC1 is highly expressed in pancreatic cancer and oral cancer cells compared with non-tumor cells. However, the expression of clock genes is not well understood in cervical cancer. In this study, we focused on the expression of DEC1, DEC2 and BMAL1 in human cervical cancer tissues, examining their expression in biopsy and surgical resection samples by immunohistochemistry. As a result, DEC1 was strongly positive in tumor cells compared with adjacent non-tumor cells. Especially, the positive cells were observed in the front lesions of the tumors, suggesting that DEC1 is associated with invasion. The positive staining of vimentin was also observed in the same lesions where DEC1 was positive. On the other hand, no obvious significant difference in DEC2 expression was observed between tumor cells and non-tumor cells. For BMAL1, we found a week staining in the tumor cells compared with non-tumor cells. In addition, we examined the expression of stem cell marker Sox2 and c-Myc in cancer tissues. They were highly expressed in tumor cells compared with the adjacent non-tumor cells. Furthermore, Sox2 was expressed in metastatic lesions higher than the primary sites. These results suggest that clock genes DEC1 and BMAL1 may promote progression of cervical cancer, regulating Sox2 and c-Myc expression.
Citation Format: Fuyuki Sato, Yasueru Muragaki. Clock genes DEC1 and BMAL1 regulate the expression of stem cell marker genes Sox2 and c-Myc in cervical 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 3355.
Abstract 3363: PUM3 is a triple-negative breast cancer dependency gene that functions in replication fork restart and repair
Authors: Weekes Daniel , Noel Elodie , Walker Callum , Balan Nick , Shah Vandna , Sidhu Bhavna , Pardix Anna , Pettitt Stephen , Lord Christopher J. , Grigoriadis Anita , Andrew Tutt N. 
Published: August 2018

Abstract
Triple-Negative Breast Cancers (TNBC) are characterized by high levels of structural chromosome alterations and harbor mutational scars of defects in homologous recombination. Importantly, by acting either as drivers, or as tumor specific dependencies mutated genes in these regions represent potential therapeutic targets
In search of such genes we identified that knockdown of the PUM3 gene, which is contained in a 9p24 recurrent ampliicon, impaired the growth of a subset of breast cancer but not mammary epithelial cell lines. Furthermore, the growth defects observed upon PUM3 knockdown in SUM149, a BRCA1 deficient cell line, were reversed by reactivation of BRCA1's function suggesting a BRCA1-deficiency associated dependency. PUM3 knockdown led to an increase in gH2Ax and 53BP1 nuclear foci, impaired restart of stalled replication forks, and decreased RAD51 mediated repair of collapsed replication forks. As a result PUM3 depleted cells have reduced DNA replication rate and slowed cell cycle progression. Knockdown of PUM3 also impaired replication stress induced PARylation and PAR foci formation and PUM3 and PARP1 knockdown showed phenotypic epistasis with respect to cell growth suggesting a potential mechanism for PUM3s replication fork related functions.
PUM3 forms a complex with gH2Ax and the replication stalling agent hyroxyurea and PARP-inhibitors increases the nuclear concentration of PUM3. Furthermore PUM3 knockdown increased the sensitivity of breast cancer cells to these agents indicating a role for PUM3 in the repair of lesions generating by these DNA damaging agents.
By studying PUM3 we have identified a novel player in replication fork restart and repair whose activity may be particularly relevant in homologous recombination deficient TNBCs. A greater understanding of PUM3's function and the pathways that regulate it may identify novel therapeutic targets for TNBCs. Importantly, direct or indirect modulation of PUM's functions may potentiate the effects of replication stress inducing therapies such as PARP-inhibitors.
Citation Format: Daniel Weekes, Elodie Noel, Callum Walker, Nick Balan, Vandna Shah, Bhavna Sidhu, Anna Pardix, Stephen Pettitt, Christopher J. Lord, Anita Grigoriadis, Tutt N. Andrew. PUM3 is a triple-negative breast cancer dependency gene that functions in replication fork restart and repair [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 3363.
Abstract 3373: Analysis of the “centrosome-ome” reveals potential causes of centrosome amplification in human cancer
Authors: Denu Ryan A. , Jagodinsky Justin C. , Burkard Mark E. 
Published: August 2018

Abstract
The centrosome is the microtubule organizing center of human cells and facilitates a myriad of cellular functions. This includes the organization of the mitotic spindle for faithful chromosome segregation during mitosis, cell polarization and migration, and primary cilia formation. A numerical increase in centrosomes, or centrosome amplification (CA), is common in cancer and correlates with aggressive clinical features and poor patient outcomes. CA is thought to arise by two major mechanisms: (1) centriole overduplication and (2) cell doubling events. To better assess the relative contributions of these two mechanisms, we analyzed 79 melanomas compared to 17 benign nevi and 60 prostate cancers compared to 20 benign prostate samples. We probed these samples for pericentrin (to mark all centrosomes) and CEP170 (to mark centrosomes with mature centrioles). CEP170 is expected on most or all amplified centrosomes with cell doubling, but not with overduplication (1 per cell expected). We find fewer CEP170-positive centrosomes in cancer samples compared to benign samples, indicating that centriole overduplication is the predominant mechanism leading to CA in human cancer. Given this finding, we next sought to identify the predominant molecular mechanisms leading to centriole overduplication. To address this question, we analyzed mutations, copy number alterations, and RNA expression data in the 366 proteins reported to localize to the centrosome using TCGA data. We identified a list of candidate centrosome proteins that are most frequently altered in cancer. Furthermore, given that cells with CA undergo cell cycle arrest unless other compensatory alterations are made, such as loss of p53, we ranked alterations in centrosome genes by the fold enrichment in p53 mutant versus p53 wild-type tumors. We identified the following candidates: CEP19, CEP72, NDRG1, PTK2, SPATC1, and TBCCD1 (gain-of-function mutations) and AKAP9, CEP76, CTNNB1, MCPH1, NEURL4, and NPM1 (loss-of-function mutations or deletion). In cellulo analysis of these candidates reveals that loss of MCPH1 (microcephalin) causes the most robust increase in centriole number. MCPH1 mutations are known to give rise to microcephaly and CA. MCPH1 gene deletions and/or mRNA downregulation (Z score &lt; 2) are seen in 5-15% of human cancers, depending on the anatomic site of the tumor. We conclude that a myriad of different alterations in centrosome genes can give rise to CA in human cancer, and that loss of MCPH1 is a common and penetrant cause of CA in human cancer.
Citation Format: Ryan A. Denu, Justin C. Jagodinsky, Mark E. Burkard. Analysis of the “centrosome-ome” reveals potential causes of centrosome amplification 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 3373.
Abstract 3375: The chromosomal instability in tumorigenesis of esophageal squamous cell carcinoma
Authors: Yan Ting , Cheng Xiaolong , Cui Yongping 
Published: August 2018

Abstract
Chromosomal instability (CIN) is the leading cause of the cell genome instability and is a common trait of more than 70% of human cancers, therefore is implicated as an initiator of tumorigenesis. More importantly, CIN may facilitate the adaptation of tumors to environmental or stromal stress and is implicated in determining tumor progression and associated with poor outcome, tumor relapse, and multi-drug resistance across a range of cancer types. The latest studies suggest that cancer is the result of micro-evolution altermate with macro-evolution. That means the cells get mutations through micro-evolution and expansion by the mutational accumulation; the cells begin to undergo macro-evolution instead of micro-evolution when encounter tumorigenic factors, and CIN will be the main driver for tumor evolution. However, studies focus on genomic signatures, especially for macro-evolutionary events, in esophageal squamous cell carcinoma (ESCC) are limited. We integrated 31 whole genomic sequencing data of ESCC samples from China to investigate underlying evolutionary characteristics in ESCC.
We combined copy number profiles of 1660 cancer specimens from 5 types of gestrointestinal tumors. Different from colorectal carcinoma, liver hepatocellular carcinoma, pancreatic adenocarcinoma and stomach adenocarcinoma, ESCC possesses largely copy number alterations, and frequent copy-number changes were not clustered in specific chromosome. In our cohort, we found whole genome doubling (WGD) that acts as one of mechanisms for polyploidy was predicted as a late event in the majority of ESCC genome. Moreover, loss of heterozygosity events was more likely to occur in chromosomes harboring tumor suppressor genes in ESCC. The 40% of neutral loss of heterozygosity events was not a result of genome doubling suggesting an alternative mechanism for neutral loss of heterozygosity formation. Importantly, deconstruction of copy number alterations extending to telomere revealed that telomere-bounded copy number alterations play a critical role for amplification/deletion of oncogenes/suppressor genes. For well-known genes SOX2, PIK3CA and TERT, almost all of their amplifications were telomere bounded, which was further confirmed in a Japanese ESCC cohort. Furthermore, we provide evidence that karyotype evolution was mostly punctuated in ESCC. Collectively, our data reveal the potential biological role of whole genome doubling, neutral loss of heterozygosity and telomere-bounded copy number alterations, and highlight macro-evolution in ESCC tumorigenesis.
Citation Format: Ting Yan, Xiaolong Cheng, Yongping Cui. The chromosomal instability in tumorigenesis of esophageal squamous cell 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 3375.
Abstract 3398: Analysis of whole transcriptome RNA-seq of large numbers of clinical FFPE samples
Authors: Newton Yulia , Golovato Justin , Johnson Mark , Rabizadeh Shahrooz , Sanborn Zack , Benz Steve , Vaske Charles J. 
Published: August 2018

Abstract
Background: We evaluate the feasibility, quality, and analytical potential of whole-transcriptome RNA-seq on over one thousand clinical FFPE tumor samples. Transcriptional profiling of RNA is used for clinical decision making in many tumor types. Clinical analysis of RNA is complicated by the common use of formalin-fixed paraffin-embedded (FFPE) tissue storage, which can cause low yield and RNA degradation.
Methods: RNA was extracted from FFPE material using commercially available kits using an RNAseH based ribodeplete. Multiple libraries per sample are sequenced using standard Illumina sequencing. Bowtie2, RSEM, and custom software are used for alignment, transcript quantification, fusion detection, and variant expression analysis.
Results: We observe a &gt;85% success rate on whole transcriptome RNA-seq on our cohort of more than 1000 samples. We find reliable transcript quantification upon successful sequencing, and on a subset of samples quantify differences between FFPE and fresh-frozen material when using ribodeplete. We also compare transcriptional profiles of clinical FFPE samples to an independent set of fresh frozen, poly-A capture samples from The Cancer Genome Atlas (TCGA) and show differences between poly-A capture and ribodeplete RNA isolation methods as well as FFPE vs. FF effects. We present a robust mapping methodology for comparison of public FF poly-A dataset to our FFPE ribodeplete samples. We demonstrate that we are able to utilize this joint gene expression space to perform site of origin prediction on FFPE samples. This is especially important for clinical application in analyzing Cancer of Unknown Primary (CUP) samples as well as detecting outlier samples whose molecular features may suggest additional therapeutic avenues. Finally, we show reliable detection of fusion transcripts from FFPE RNA-seq material from whole-transcriptome analysis and expression of somatic tumor variants detected from DNA sequencing.
Conclusions: Large scale sequencing of RNA from clinical FFPE materials provides reliable transcriptomic results comparable to existing public databases of RNA, enabling research on cohorts of tumors that are FFPE-banked and unavailable as frozen tissue.
Citation Format: Yulia Newton, Justin Golovato, Mark Johnson, Shahrooz Rabizadeh, Zack Sanborn, Steve Benz, Charles J. Vaske. Analysis of whole transcriptome RNA-seq of large numbers of clinical FFPE samples [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 3398.
Abstract 342: Strigolactone analogues show potential as new combination therapy agents against pancreatic cancer
Authors: Park Matthew D. , Haake Jefferson M. , Parasido Erika , Albanese Christopher , Yarden Ronit I. 
Published: August 2018

Abstract
There is an increasing appreciation for combination therapy of antineoplastic drugs that target key pathways often through a synergistic effect, reducing the chance for tumor growth, self-renewal of cancer stem cell (CSC), spread of metastasis and drug resistance. The combination of DNA repair impairment and DNA damage was shown to be a successful approach. Previously, we had shown that strigolactone (SLs; synthetic analogues, SLAs), a novel class of phytohormones, causes DNA double strand breaks (DSBs) and inhibits breast and osteosarcoma cancer cells and CSC viability. Here, we tested whether SLAs inhibit the growth of pancreatic ductal adenocarcinoma (PDAC) cells and stem cells and whether SLAs sensitize the effects of Gemcitabine (Gemzar), the most commonly prescribed drug for PDAC patients. We show that SLAs induce DSBs in different PDAC cells and the combination of SLAs with Gemcitabine significantly increases apoptosis when compared to PDAC cells treated with Gemcitabine alone. This additive effect is independent of BRCA2 expression, which suggests that SLAs are effective at impairing multiple repair mechanisms and is suitable in combination with multiple DNA damaging agents. Interestingly, we show that SLAs sensitize patient-derived Gemcitabine non-responsive, PDAC Conditionally-Reprogrammed Cells (CRCs) to Gemcitabine, reducing their overall viability by more than 30%. Accordingly, the SLA- Gemcitabine combination has a significant impact on tumorsphere (CSCs) growth outcome. These findings demonstrate the potential for a novel drug combination of SLAs and Gemcitabine and underscore the potential of SLAs for multiple highly valuable translational applications regarding alternative therapies to combat cancer.
Citation Format: Matthew D. Park, Jefferson M. Haake, Erika Parasido, Christopher Albanese, Ronit I. Yarden. Strigolactone analogues show potential as new combination therapy agents against pancreatic 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 342.
Abstract 3427: Gatekeeper inactivation drives glioma progression into secondary glioblastoma
Authors: Granberg Kirsi Johanna , Annala Matti , Jaatinen Serafiina , Haapasalo Joonas , Yli-Harja Olli , Haapasalo Hannu , Zhang Wei , Nykter Matti 
Published: August 2018

Abstract
&lt;Glioblastoma (GBM) is the most common and lethal form of brain cancer in humans. Median survival is 15 months with best available treatment. Most GBMs arise de novo (primary GBM), but 5 - 10% progress from lower grade gliomas (secondary GBM). As progression of low grade glioma into secondary GBM significantly impacts prognosis, a better understanding of this process is paramount for treatment and monitoring of affected patients. In this study, we applied whole genome and transcriptome sequencing to primary glioma and relapsed secondary GBM tissue from seven patients with progression. All primary gliomas carried IDH1 mutations, and in all cases the mutation was inherited by the secondary GBM. ATRX alterations in all five astrocytomas and TERT promoter mutations in both 1p19q-codeleted oligoastrocytomas were also inherited in progressed tumors. In five patients, progression was associated with increased genomic instability, whereas mutation load was significantly increased in two other patients. One of them exhibited a hypermutation signature caused by a mutation in the proofreading domain of DNA polymerase epsilon, while the second had lost both copies of the DNA mismatch protein MSH2. In addition, both 1p19q-codeleted tumors had acquired focal inactivating deletions of the protein tyrosine phosphatase PTPRD at progression, suggesting a novel driver mechanism for GBM progression. The most common progression-related genomic alterations were CDKN2A deletions, TP53 mutations, RB1 deletions, PTEN deletions, and deletions of genes crucial to the double strand break repair pathway. Taken together, progression into secondary GBM was significantly related to deletions in tumor suppressor genes as well as TP53 mutations. Disruption of these gatekeepers appears to be a significant mechanism for glioma progression.&gt;
Citation Format: Kirsi Johanna Granberg, Matti Annala, Serafiina Jaatinen, Joonas Haapasalo, Olli Yli-Harja, Hannu Haapasalo, Wei Zhang, Matti Nykter. Gatekeeper inactivation drives glioma progression into secondary glioblastoma [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 3427.
Abstract 3441: Genome-wide gene expression analysis in asbestos-related non-small cell lung cancer
Authors: Kettunen Eeva , Marwah Veer Singh , Wolff Henrik , Greco Dario , Husgafvel-Pursiainen Kirsti 
Published: August 2018

Abstract
Recently we examined genome-wide DNA methylation in lung cancer from patients occupationally exposed to asbestos (Kettunen et al 2017 Int J Cancer). Distinct methylation changes in lung tumors were shown in relation to asbestos exposure and tobacco smoking. Now we have performed genome-wide gene expression microarray experiments with Agilent SurePrint G3 Human GE 8x60K v3 Microarrays using same samples. Patients had been interviewed for work and smoking histories and their pulmonary asbestos fiber counts were measured by electron microscopy. Fresh-frozen lung cancer tissues (LC, n=42) and paired microscopically normal peripheral lung tissues (NT, n=21) were studied. After data processing and analyses for differential gene expression, data were filtered for adjusted p &lt; 0.05 and fold change &gt; 1.5. Principal component analysis showed distinct clusters of normal lung and cancer tissues. In lung cancers compared with their paired microscopically normal lung, 5931 genes such as those involved in neutrophil degranulation and immune system were differentially expressed, with the lowest adjusted p=6.71E-37. In our preliminary analyses, 34 genes in NT and 44 in LC, and 152 genes in NT and 12 in LC showed differential expression when the asbestos-exposed were compared to non-exposed and current smokers to ex-smokers, respectively. The genes differentially expressed in relation to smoking or to asbestos exposure had the lowest adjusted p=8.50E-06 and 9.83E-04, respectively. Within differential gene expression related to asbestos exposure, chemokine activity and regulation of cellular protein metabolic processes were implicated whereas microtubules and positive regulation of transcription were related with tobacco smoking burden. In conclusion, comparison of gene expression patterns between lung cancer tissue and paired normal lung showed distinct principal component analysis clusters. Our preliminary data suggest different major biological processes in gene expression for these exposures. Financial support from the Cancer Society of Finland (2014 and 2015) is gratefully acknowledged.
Citation Format: Eeva Kettunen, Veer Singh Marwah, Henrik Wolff, Dario Greco, Kirsti Husgafvel-Pursiainen. Genome-wide gene expression analysis in asbestos-related non-small cell lung 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 3441.