bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 34: Identification of a phosphorylation cascade triggering Wnt/planar cell polarity signaling in breast cancer cells
Authors: Borg Jean-Paul 
Published: August 2018

Abstract
The developmental Wnt/planar cell polarity (PCP) pathway is the most recently described branch of Wnt signaling strongly implicated in cancer development at early and late stages. Upregulation of Wnt/PCP components and signaling is indeed observed in many cancers, this event being mostly associated with cancer progression. However, how the function of this signaling is remains presently an open question. Recent work in our laboratory found that Prickle1 and Vangl2, two core Wnt/PCP components, are overexpressed in triple negative breast cancers and associated with poor prognosis. Prickle1 is a cytoplasmic PET/LIM-containing protein phosphorylated by the serine/threonine kinase Mink1 which triggers Prickle1 localization at the plasma membrane and regulates its activity. Activation of the Prickle1-Mink1 axis promotes breast cancer cell motility and metastatic spreading in the mouse by promoting β1-integrin turn-over, focal adhesion dynamics and cytoskeleton remodeling. However, Prickle1 is probably not the unique substrate of Mink1 in breast cancer cells. Through a combination of protein purification and mass spectrometry analysis, we identified novel partners of the Prickle1-Mink1 complex which includes LL5β, a PH domain containing protein involved in β1-integrin turn-over. In parallel, by an independent approach looking for Mink1 substrates in breast cancer cells, we identified LL5β as a potential substrate for this poorly described protein kinase. Using recombinant LL5β and Prickle1, we confirmed that Mink1 can directly phosphorylate both proteins in in vitro kinase assays. We also defined that, in breast cancer cells, Mink1 associates with and phosphorylates LL5β, controlling its subcellular localization, a key step for cancer cell motility. Our data provide novel insights on the regulation of the prometastatic Wnt/PCP pathway by characterizing an yet unknown multi-step phosphorylation cascade with promising targeting potential.
Citation Format: Jean-Paul Borg. Identification of a phosphorylation cascade triggering Wnt/planar cell polarity signaling in breast cancer cells [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 34.
Abstract 3405: A mutational signature associated with alcohol consumption and prognostically mutated driver genes in esophageal squamous cell carcinoma
Authors: Li Xiangchun , Wang Mengyao , Yang Meng , Dai Hongji , Zhang Baifeng , Wang Wei , Chu Xinlei , Wang Xin , Zheng Hong , Niu Ruifang , Zhang Wei , Chen Kexin 
Published: August 2018

Abstract
Aim: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. Herein, we elucidated significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC.
Methods: Three MutSig algorithms (i.e. MutSigCV, MutSigCL and MutSigFN) and “20/20” ratio-metric were employed to identify SMGs. Nonnegative matrix factorization was used to decipher mutational signatures. Kaplan-Meier survival analysis, multivariate Cox and logistic regression models were applied to analyze association between mutational features and clinical parameters.
Results: We identified 26 SMGs, including 8 novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8 and BAP1) and 18 previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike C&gt;T at CpG, APOBEC overactive C&gt;T at TpCp[A/T], and a signature featured by T&gt;C substitution. The T&gt;C mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P &lt; 0.001). This alcohol consumption signature was also observed in liver cancer and head and neck squamous cell carcinoma, and its mutational activity was substantially higher in samples with mutations in TP53. Survival analysis revealed that TENM3 mutations (HR: 5.54; CI: 2.68-11.45; P &lt; 0.001) and TP53 hotspot mutation p.R213* (HR: 3.37; CI: 1.73-8.06; P &lt; 0.001) were significantly associated with shortened survival outcome. The association remained statistically significant after controlling for age, gender, TNM stage and tumor grade.
Conclusions: We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutation and TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.
Citation Format: Xiangchun Li, Mengyao Wang, Meng Yang, Hongji Dai, Baifeng Zhang, Wei Wang, Xinlei Chu, Xin Wang, Hong Zheng, Ruifang Niu, Wei Zhang, Kexin Chen. A mutational signature associated with alcohol consumption and prognostically mutated driver genes in 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 3405.
Abstract 3410: Copy number estimation from whole-exome sequencing in tumors
Authors: Anderson Shawn , Che Zhiwei , Keshavan Raja , O'Hara Andrea , Lin Dong , Wang Yuzhuo , Collins Colin , Shams Soheil 
Published: August 2018

Abstract
At the Vancouver Prostate Centre (VPC), a personalized medicine approach is the focus to the understanding and treatment of prostate and other cancers. As a part of this approach, the xenograft program is used to identify and validate mechanisms and drivers of progress and therapeutic targets. VPC frequently uses Next-Generation Sequencing (NGS) technologies for copy number (CN) analysis. Many CN from NGS algorithms require a matched normal reference for CN estimation, however, a matched normal may not be possible for many reasons including unavailability of patient blood sample and poor quality of the matched sample in question. The correct CN algorithm for NGS data is critical to overcome these obstacles. Here we will share our results from analysis of Whole Exome Sequencing (WES) of prostate cancer patient-derived xenograft (PC PDX) samples using Nexus Copy Number software with BioDiscovery's BAM MSR algorithm. A pooled reference can be created using unmatched normal samples; however, when normal samples are not available, tumor samples from within the batch and/or run can be used to create a reference. BAM MSR derives CN and B-Allele Frequency (BAF) from WES, whole-exome sequencing (WGS), and targeted panels using a pooled reference. Due to an absence of normal samples, randomly selected tumor samples were used to build a reference file, which was used for baseline CNV results. By using a recursive refinement method, which incorporated evaluation of B-allele frequency (BAF) patterns among the pooled samples, a subset of tumor samples was selected to create a refined pooled reference using BAM MSR. All tumor samples were then subjected to CN estimation, which included adjustment based on tumor ploidy. While creating a normal reference including PC PDX tumor samples may seem counter intuitive due to enrichment of cancer cells and replacement of stromal component with mouse origin (e.g. fibroblasts, endothelium and immune cells), and high early recurrent copy number signatures, the BAM MSR algorithm was able to get results comparable to previous aCGH results. This is of special importance because the lack of normal tissues is commonplace in cancer research.
Citation Format: Shawn Anderson, Zhiwei Che, Raja Keshavan, Andrea O'Hara, Dong Lin, Yuzhuo Wang, Colin Collins, Soheil Shams. Copy number estimation from whole-exome sequencing in tumors [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 3410.
Abstract 3412: Androgen receptor binding sites are highly mutated in prostate cancer
Authors: Morova Tunc , Gonen Mehmet , Gursoy Attila , Keskin Ozlem , Lack Nathan A. 
Published: August 2018

Abstract
Androgen receptor (AR) signaling is essential to nearly all prostate cancer cells. Any alterations to AR-mediated transcription can have a profound effect on prostate carcinogenesis and tumor growth. While the AR protein has been extensively studied, little is know about those mutations to non-coding regions where AR binds to DNA. Using whole genome sequencing from 197 primary prostate cancer patients, we demonstrate that AR binding sites have a dramatically increased rate of mutations that is greater than any other transcription factor. This is not due to the specific chromosomal region as increased mutation were only observed in prostate cancer. The rate of mutations correlated with AR occupancy and did not cluster with any histone mark or transcription factor. Suggesting that this may occur with other lineage-specific transcription factors, we observed that estrogen receptor binding sites also had an elevated rate of mutations in breast cancer. Interestingly, the mutations at AR binding sites had a high frequency of TpG-&gt;ApG. These uncommon purine transversions have been shown to occur when abasic sites are incorrectly repaired. Based on the mutations observed at the binding site of AR and other related transcription factors, we propose that AR occupancy impairs access of base excision repair enzymes to endogenous DNA damage. Overall, this work demonstrates that non-coding AR binding sites are frequently mutated in prostate cancer and may potentially act as driver mutations.
Citation Format: Tunc Morova, Mehmet Gonen, Attila Gursoy, Ozlem Keskin, Nathan A. Lack. Androgen receptor binding sites are highly mutated in prostate 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 3412.
Abstract 3421: Genomic correlates of patient age in diffuse-type gastric cancer
Authors: Kim Hark K. , Cho Soo Y. 
Published: August 2018

Abstract
Background: Gastric cancer is increasing in incidence among young white populations in the US. Gastric cancer in young patients is notable for its enrichment of diffuse histology as well as female predominance and aggressive clinical course, whereas gastric cancer is generally more frequent in males. Thus, clinicopathological characteristics of diffuse-type gastric cancer differ according to patient age, but the molecular mechanisms for early-onset gastric cancer's unique clinicopathological characteristics have not been elucidated. While the incidence of intestinal-type gastric cancer is decreasing worldwide, that of diffuse-type gastric cancer remained constant. Nonetheless, relatively small numbers of diffuse-type gastric cancers have been represented in whole exome sequencing studies such as TCGA project. We therefore investigated germline and somatic mutation profiles of diffuse-type gastric cancers with regards to patient age.
Methods: We conducted whole exome and targeted sequencing and SNP6.0 array analyses of resected tumor tissue and blood samples collected from young (45 years old or younger) Korean patients with diffuse-type gastric cancer, and compared the genomic data with those from older Korean patients with diffuse-type gastric cancer. Genomic data of Korean diffuse-type gastric cancers were also compared with TCGA diffuse-type gastric cancers, 70% of which were from Caucasians.
Results: Among 84 young Korean patients with DGC, 7 patients (8.3%) harbored germline mutations in TP53, CDH1, ATM, RAD51D, or PALB2. Three tumors with strong mutation signatures for inherited DNA repair defects harbored germline mutations in either RAD51D or PALB2, with loss-of-heterozygosity in the tumors. The most significant somatic mutations in young patients with diffuse gastric cancer were CDH1, TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. Within the Korean population and within populations of other ethnicities, mutations in CDH1 (42.2%) or TGFBR1 (7.3%) were more frequent in younger patients than in older patients (17.4% and 0.9%, respectively). In contrast, the RHOA mutation (9.2%) was less frequent in younger patients than in older patients (19.1%). CDH1 alterations, but not RHOA mutations, were associated with poor prognosis (hazard ratio, 3.4 (95% CI, 1.5-7.7)), which may be associated with the aggressive clinical course of diffuse-type gastric cancers in young patients.
Conclusions: Our largest-ever genomic analysis of diffuse-type gastric cancer reveals young age-specific mutation profiles (supported by National Cancer Center Grant 1710809 and Multi-omic Research Program).
Citation Format: Hark K. Kim, Soo Y. Cho. Genomic correlates of patient age in diffuse-type gastric 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 3421.
Abstract 3425: Exome-sequencing derived mutations of endocrine treated ER-positive early breast cancer
Authors: Schroth Werner , Kandabarau Siarhei , Fritz Peter , Mürdter Thomas , Bacchus Liza , Group German Tamoxifen Study , Schwab Matthias , Brauch Hiltrud 
Published: August 2018

Abstract
Anti-hormonal treatment of ER-positive early breast cancer with tamoxifen and/or aromatase inhibitors (AI) significantly improves patient outcome, however there is a lack of markers that predict the one third of treated patients who relapse or die. Although ER positive (luminal) tumors are known to be genetically highly diverse, the relevance of somatic mutations with regards to endocrine treatment outcome and course of the patients' disease is not fully understood. We conducted a prospective observational clinical trial for the investigation of treatment outcome determinants including 1219 tamoxifen and/or AI-treated postmenopausal ER-positive early breast cancer patients (DRKS00000605, recruitment between 2005-2010, median follow up 5.1 years). Of these, 40 tumors divided into 20 patients each with and without disease recurrence matched by prognostic variables (age, tumor size, grade, nodal status, treatment) were analyzed for their mutation pattern. We performed whole-exome sequencing of tumor and normal DNA (Agilent SureSelect, Illumina) for the identification of single nucleotide variants and small indels. Somatic mutations were identified following subtraction of germline single nucleotide polymorphisms (SNP), filtering based on raw-read quality parameters, in silico predicted biological function, and disease relatedness using the Ingenuity variant analysis software package (Qiagen). Clinical outcome associations were tested either on gene or on variant level. Somatic mutations with predicted deleterious effects were identified in 18 out of 40 known mutation-driver genes including PIK3CA, GATA3, MAP3K1, and TP53 (45%). Thirteen patients carried a mutation in the most frequently affected PIK3CA (32.5%). Of note, three out of four patients with a E542K mutation belonged to the breast cancer recurrence group, while 5 of 6 tumors with the H1047R mutation originated from patients without recurrence suggesting differential effects of these PIK3CA hotspot mutations. Common germline SNPs at IL17RB, ANK2, POM121, PGR, PTPRB, RAD51D, RFPLA4, and SUMO3 provided first hints for a possible association with relapse status (p&lt;0.05). We will report on the extended genotype-outcome-correlations to further evaluate the relevance of somatic mutations for endocrine treatment outcome of early ER-positive breast cancer.
Citation Format: Werner Schroth, Siarhei Kandabarau, Peter Fritz, Thomas Mürdter, Liza Bacchus, German Tamoxifen Study Group, Matthias Schwab, Hiltrud Brauch. Exome-sequencing derived mutations of endocrine treated ER-positive early breast 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 3425.
Abstract 3428: Development and validation of the plasma monitor test system
Authors: Kelly Kevin J. , Uvalic Jasmina , Bergeron Daniel , Burns Shelbi , Soucy Melissa , Ananda Guruprasad , Hesse Andrew , Selvam Pavalan Panneer , Reddi Honey V. 
Published: August 2018

Abstract
Introduction: Non-invasive monitoring of variants in a cancer patient for minimal residual disease, recurrence and/or resistance has tremendous clinical utility and warrants the development of a cell-free circulating tumor DNA panel, which involves the use of a simple blood draw. Towards this end, JAX has validated a new liquid biopsy assay called the Plasma MonitorTM that focuses on 84 clinically significant hotspots across 14 genes to complement our current clinical test menu, with a focus on comprehensive profiling of cancer.
Methods: Post development and optimization of a custom amplicon panel, which included running multiple batches of samples through the assay to determine appropriate extraction methods, input DNA QC metrics, sequencing batch size, and sequencing loading concentrations, clinical validation of The Plasma MonitorTM was initiated. Validation included the evaluation of 20 uncharacterized plasma samples and 14 known controls and was executed in 5 phases: (1) Sample Processing for Validation Parameter determination; (2) LOD, sensitivity, specificity and accuracy (3) inter-assay concordance; (4) intra-assay concordance; (5) clinical validity in terms of interpretation and reporting of variants identified.
Results: The final clinical protocol was developed using an input of 10ng of ctcfDNA quantified and qualified by a custom qPCR assay. Wet lab results of the first validation batch can be seen in Table 1. Using samples containing variants with known allele frequencies and a droplet digital PCR (ddPCR) based confirmation of novel variants identified by our assay, we established the assay's limit of detection (LOD) to be 0.9%. At this LOD, sensitivity, specificity, and accuracy were found to be 96.6%, 100%, and 98% respectively.
Conclusion: Based on the results of this validation, the Plasma Monitor assay will be incorporated into the JAX clinical test menu. This new assay allows for comprehensive profiling and monitoring of cancer progression, response to therapy and minimal residual disease, and a significant benefit to both patients and clinicians.
Citation Format: Kevin J. Kelly, Jasmina Uvalic, Daniel Bergeron, Shelbi Burns, Melissa Soucy, Guruprasad Ananda, Andrew Hesse, Pavalan Panneer Selvam, Honey V. Reddi. Development and validation of the plasma monitor test system [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 3428.
Abstract 3434: Digital spatial profiling platform allows for spatially resolved, high-plex quantification of mRNA distribution and abundance on FFPE and fresh frozen tissue sections
Authors: Zollinger Daniel , Sorg Kristina , McKay-Fleisch Jill , Barker Kristi , Nguyen Karen , Merritt Chris , Beechem Joseph 
Published: August 2018

Abstract
Characterization of spatial mRNA expression across multiple targets in a single tissue section has proven difficult to accomplish. To address this unmet need, we have developed a novel imaging platform, Digital Spatial Profiling (DSP), designed to simultaneously analyze 10s to 100s of RNAs (or proteins) from discrete regions by detecting oligo-conjugated probes. We show that this system can resolve mRNA expression panels in a highly multiplexed and automated manner on human FFPE and fresh frozen tissues. DSP RNA probes consist of antisense target-recognition sequences and UV-cleavable tags that can be released in a precise manner by the DSP instrument and digitally counted using nCounter® reagents. For this, probes are first hybridized overnight in situ to human FFPE or fresh frozen tissue sections. After hybridization, tags are released by nondestructive exposure of UV light, automatically collected by the DSP Instrument, and quantified using nCounter® technology. The nCounter PlexSet™ reagents are used to enable the analysis of 96 regions of interest with a single nCounter run. To demonstrate the regional specificity of RNA detection on DSP, we profiled distinct regions in human tonsillitis tissues using a 48-plex of RNA target probes. Our results show that genes are detected in the expected region-specific manner. Using an orthogonal in situ hybridization (ISH) approach, we validate the RNA DSP results in tonsil across multiple targets. To determine the regionally specific RNA expression in tumor area and nontumor area in non-small cell lung cancer (NCSLC), we used a high-plex probe mix of relevant Immuno-oncology RNA targets. These results show that the DSP platform can be used to obtain high-plex, spatial RNA expression data on tissue sections. The protein profiling assay on DSP, presented elsewhere, depends upon FFPE-compatible antibodies, which can be difficult to generate for some targets. Utilizing spatial mRNA profiling provides an alternative for cases where the necessary antibodies do not exist. In all, simultaneous, high-plex RNA and protein detection with DSP on serial sections could provide a novel method that can bridge the gap between translational research discovery and clinical applications.
Citation Format: Daniel Zollinger, Kristina Sorg, Jill McKay-Fleisch, Kristi Barker, Karen Nguyen, Chris Merritt, Joseph Beechem. Digital spatial profiling platform allows for spatially resolved, high-plex quantification of mRNA distribution and abundance on FFPE and fresh frozen tissue sections [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 3434.
Abstract 3439: GATA3 mutation of luminal-type breast cancer patients in Taiwan
Authors: Tsai Shih Feng 
Published: August 2018

Abstract
To investigate the mutation landscape of luminal-type breast cancer in Taiwan, we have conducted whole-genome sequencing on 20 cases of breast cancer, including 15 cases of those positive for estrogen receptor and 5 cases negative for estrogen receptor. Specifically, we searched for mutations in TP53, GATA3, and ESR1 genes. Additionally, we designed an amplificon sequencing scheme to interrogate the GATA3 coding sequences. GATA3 mutation has been previously reported to be correlated with suppression of proliferation upon aromatase inhibitor treatment. Also, the prevalence and clinical significance of GATA3 mutation-positive breast cancer differed between the TCGA cohort and the Fudan cohort. In our current series that focuses on breast cancer patients of Han Chinese living in Taiwan, we have identified 21 GATA3 mutations among 72 breast cancer tumor specimens screened by the amplicon sequence, and another 3 samples with GATA3 mutation by whole-genome sequencing. Notably, Pro409Alafs mutation occurred in six cases and this truncation mutation showed an average VAF of 0.155. A specific antibody was raised against the additional c-terminal amino acid sequence for the detection of the abnormally expressed proteins in these cases. As GATA3 is required for epithelial cell differentiation and as both normal breast luminal epithelium and estrogen-receptor-positive tumors showed high GATA3 expression, we are conducting further studies to demonstrate the clinical relevance of GATA3 mutation and the potential value of the Pro409Alafs as an outcome predictor for luminal-type breast cancer.
Citation Format: Shih Feng Tsai. GATA3 mutation of luminal-type breast cancer patients in Taiwan [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 3439.