bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5300: smCounter2, a highly accurate UMI-aware variant caller and its applications in detecting 0.5-1% somatic mutations using targeted panel sequencing
Authors: Xu Chang , Gu Xiujing , Wu Zhong , DiCarlo John , Wang Yexun 
Published: August 2018

Abstract
We introduce smCounter2, our new version of low-frequency variant caller for targeted panel sequencing data. Upgraded from the previous version of smCounter (Xu et al, BMC Genomics, 2017), smCounter2 has a higher accuracy of detecting 0.5-1% variants and a more solid and scalable theoretical foundation. For 1% SNVs, smCounter2 achieved above 98% sensitivity and fewer than 10 false positives per megabase on a 680kb custom panel using a mixture of Genome in a Bottle reference samples. For 0.5% SNVs (including multi-allelic variants), smCounter2 achieved 87.5% sensitivity (7 out of 8) using a mixture of Horizon Tru-Q samples. We have also tested smCounter2 on other datasets with 5% and germline variants. On all these datasets except the germline variants, smCounter2 has demonstrated superior performance compared with other state-of-the-art UMI-aware variant calling algorithms. Currently, we are generating data on another custom panel (~900kb) to demonstrate the sensitivity and specificity of calling 0.5% variants.
smCounter2 models DNA polymerase errors for each substitution type, therefore more accurately distinguishes real variants from the first-cycle PCR errors, which cannot be corrected by UMIs. smCounter2 is equipped with model-based filters that can reduce false calls in repetitive regions such as homopolymers and micro-satellite sequences, where error rate is generally higher and UMIs tend to be less effective. These features, to some extent, overcome the intrinsic limitations of UMI-based variant calling and are essential to smCounter2's improved performance.
Citation Format: Chang Xu, Xiujing Gu, Zhong Wu, John DiCarlo, Yexun Wang. smCounter2, a highly accurate UMI-aware variant caller and its applications in detecting 0.5-1% somatic mutations using targeted panel sequencing [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 5300.
Abstract 5308: Using RNA expression data for splicing variant assessment and confirmation
Authors: Lund Jim , Bailey Shannon , Gujja Sharvari , Gulcher Jeffrey 
Published: August 2018

Abstract
Nine percent of disease-causing mutations classified in HGMD have the potential to impact RNA splicing. Splicing variants called from DNA sequence data, especially variants outside the canonical splice site, are difficult to evaluate clinically as they often have no effect on protein expression. A method to utilize RNA-Seq data for splice site variant classification was developed. RNA reads aligned to the region of a splice site variant are examined to determine if RNA read through is present which indicates normal splicing at the site is disrupted.
Thousands of paired tumor and normal TCGA DNA and RNA samples were used to evaluate the algorithm and rule out alternate splicing in the tissue as explanation for RNA read through. Splicing variants can also alter exon usage and RNA isoform expression, and this can be identified by examining RNA isoform expression. An analysis of splicing variants in the TCGA project datasets has generated sets of confirmed functional and non-disruptive splicing varaints. This splicing dataset can be used to test and refine splicing defect prediction algorithms.
Citation Format: Jim Lund, Shannon Bailey, Sharvari Gujja, Jeffrey Gulcher. Using RNA expression data for splicing variant assessment and confirmation [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 5308.
Abstract 5312: The effect of Dnmt1 overexpression on intestinal tumorigenesis
Authors: Schaaf Nicole A. Vander , Park JinA , Dina Oluwasei , Lee KwangHo , Laird Peter W. 
Published: August 2018

Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Strong genetic drivers of tumorigenesis, such as loss of function of the APC tumor-suppressor gene, have been well characterized, but the role of epigenetic alterations remains poorly understood. Upregulation of DNA methyltransferases (DNMTs), including DNMT1, has been reported in various human cancers, but its functional significance to cancer is unclear. Here we report a novel mouse model of inducible Dnmt1 upregulation, bypassing the embryonic lethality of Dnmt1 overexpression. We accomplish inducible control of Dnmt1 expression by targeting the tet transcriptional activator to the endogenous Dnmt1 promoter. We combine this model with the ApcMin allele to investigate the effect of Dnmt1 upregulation on intestinal tumorigenesis. Our preliminary data suggests that Dnmt1 overexpression increases the size and multiplicity of intestinal polyps in ApcMin/+ mice. Previous work in our lab showed that DNA methylation is critical for tumor formation, but it is not known which DNA methylation alterations have functional relevance. To investigate this, we will use the Dnmt1 overexpression model to identify DNA methylation events that are responsible for the observed phenotype in ApcMin/+ mice. In summary, we describe a novel mouse model of Dnmt1 overexpression and provide preliminary evidence to suggest that such upregulation exacerbates intestinal tumorigenesis. Our investigation may yield new insights into the role of epigenetics in CRC initiation and progression and into potential epigenetic therapies.
Citation Format: Nicole A. Vander Schaaf, JinA Park, Oluwasei Dina, KwangHo Lee, Peter W. Laird. The effect of Dnmt1 overexpression on intestinal tumorigenesis [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 5312.
Abstract 5319: Genetic regulation of DNA methylation in breast cancer
Authors: Lin Nan , Shendre Aditi , Liu JinPeng , Wang Chi , Liu Yunlong , He Chunyan 
Published: August 2018

Abstract
Aberrant DNA methylation plays an important role in breast cancer initiation and progression. It is believed that changes in DNA methylation occur early in breast cancer development or even in normal tissue before tumor occurrence, and these changes could be a useful source for early detection, prognosis, and targeted therapy. DNA methylation is tissue-specific and is influenced by inherited genetic variations in the human genome. Genome-wide association studies (GWAS) have identified more than 600 single nucleotide polymorphisms (SNPs) associated with breast cancer risk and outcome. However, how these germline genetic variants influence DNA methylation in breast tissue, especially in normal breast tissue, remains largely unknown. We performed a methylation quantitative trait loci (meQTL) analysis to examine the association between the GWAS identified breast cancer risk loci and DNA methylation in 48 women with paired blood and breast tissue samples. Genotyping of SNPs was performed using blood-derived DNA and the Illumina HumanOmni 2.5-4v1_D array chip. Genome-wide DNA methylation was measured using breast tissue derived genomic DNA and the new Illumina TruSeq Methyl Capture EPIC sequencing technology. We found that GWAS-identified breast cancer risk loci were associated with DNA methylation sites close to genes enriched in pathways related to cell differentiation and morphogenesis, DNA damage, cell movement, and hormonal signaling pathways. We identified more cis-acting than trans-acting meQTLs, and the peak enrichment for meQTLs was in close proximity to transcription start sites. We further compared our results with those from the meQTL studies conducted with lymphoblastoid cell lines and peripheral blood samples. We found more than 60% of the identified association between genetic variants and DNA methylation in our study are tissue-type specific. Our study may provide a post-GWAS functional characterization of breast cancer risk loci and shed light on epigenetic mechanisms that underlie the observed GWAS association.
Citation Format: Nan Lin, Aditi Shendre, JinPeng Liu, Chi Wang, Yunlong Liu, Chunyan He. Genetic regulation of DNA methylation in 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 5319.
Abstract 5332: Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer
Authors: Imai Atsushi , Misawa Kiyoshi , Mochizuki Daiki , Mineta Hiroyuki , Kanazawa Takeharu 
Published: August 2018

Abstract
Staging and pathological grading are useful, but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Accordingly, molecular biomarkers that predict the risk of recurrence are necessary to improve clinical outcomes. The ability to distinguish between low- and high-risk HNSCCs at an early stage may reduce follow-up costs. We hypothesized that the quantitative methylation specific PCR (Q-MSP) assay could be used to define patterns of DNA methylation that differentiate low- and high-risk HNSCCs. The methylation statuses of the promoters of 11 tumor-related genes (p16, RASSF1A, E-cadherin, H-cadherin, MGMT, DAPK, DCC, COL1A2, TAC1, SST, and GALR1) were analyzed in 133 HNSCC cases using quantitative methylation-specific PCR. Frequent methylation of p16 (44%), RASSF1A (18%), E-cadherin (53%), H-cadherin (35%), MGMT (35%), DAPK (53%), DCC (42%), COL1A2 (44%), TAC1 (61%), SST (64%), and GALR1 (44%) in HNSCC were detected. Disease-free survival was lower in patients with 6-11 methylated genes than in those with 0-5 methylated genes (log-rank test, P = 0.001). In a multivariate Cox proportional hazards analysis, the methylation of E-cadherin, COL1A2, TAC1, and GALR1 was associated with poor survival, with hazard ratios of 4.474 (95% CI, 1.241-16.124). In a joint analysis of these four genes, patients with 2-4 methylated genes had a significantly lower survival rate than those with 0-1 methylated genes in early-stage HNSCC. Importantly, the methylation of some genes was closely related to poor prognosis in early-stage HNSCC, providing strong evidence that these hypermethylated genes are valuable biomarkers for prognostic evaluation. In conclusion, the methylation profiles of E-cadherin, COL1A2, TAC1, and GALR1 were the most powerful combination for predicting early-stage HNSCC. This demonstrates that molecular stratification may predict cancer progression. These findings can benefit HNSCC screening and surveillance algorithms. Although our study was retrospective, was conducted at a single institution, and the number of patients was small, it serves as a platform to establish optimal therapeutic strategies for early-stage HNSCC.
Citation Format: Atsushi Imai, Kiyoshi Misawa, Daiki Mochizuki, Hiroyuki Mineta, Takeharu Kanazawa. Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck 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 5332.
Abstract 5336: Methylation patterns in hepatoblastoma: A report from the Children's Oncology Group
Authors: Marcotte Erin , Spector Logan G. , Nelson Heather , Tomlinson Gail , Krailo Mark , Mills Lauren , Poynter Jenny 
Published: August 2018

Abstract
Introduction. Hepatoblastoma (HB) accounts for over 80% of all liver cancer diagnosed in children under 15 years of age in the United States. Aberrant DNA methylation has been implicated in the pathogenesis of multiple types of cancer, including HB. Global hypomethylation and DNA methylation in the promoter region of selected tumor suppressor genes, including RASSF1A, p16, SOCS1, CASP8, and MT1G, has been observed in previous studies of HB. Methods. A total of 47 flash-frozen samples of HB tumors were available for analysis. These tumors include 26 tumors from cases enrolled in Children's Oncology Group study AEPI04C1 (the HOPE study) and 21 tumors obtained as part of the Children's Oncology Group P9346 HB biology protocol. The Cooperative Human Tissue Network Pediatric Division (CHTN; Columbus, OH) provided 23 normal liver tissue samples from children ages 0—6 to serve as controls in this analysis. Initial multi-dimensional scaling (MDS) plots showed that 8 samples, 2 control and 6 patients, did not cluster with the other samples of the same group and were considered outliers. These 8 samples were removed from the study leaving a total of 62 samples, 21 control and 41 patients, remaining. Differentially methylated regions (DMR) were identified between control and patient samples using the bumphunter algorithm included in the minfi package. We used Ingenuity Pathway Analysis (IPA) to identify pathways that were enriched in the group of CpG with a change in methylation beta value of ≥39% between patients and controls. Results. We found 4833 DMR, which are associated with 3543 genes, when comparing HB patients and controls. Pathway analysis revealed 76 pathways enriched among the DMR. Conclusions. Identification of methylation patterns may elucidate the developmental stage at which HB arose and the at-risk period when environmental exposures could be most harmful. Further, understanding the relevant genetic pathways could lead to the development of new targets for therapy.
Citation Format: Erin Marcotte, Logan G. Spector, Heather Nelson, Gail Tomlinson, Mark Krailo, Lauren Mills, Jenny Poynter. Methylation patterns in hepatoblastoma: A report from the Children's Oncology Group [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 5336.
Abstract 537: CK1 delta as a therapeutic target in bladder cancer
Authors: Chen Chun-Han 
Published: August 2018

Abstract
Bladder cancer is a common malignancy worldwide, but targeted therapy is currently unavailable. Therefore, there is an unmet medical need for bladder cancer patients. Oncomine database revealed that gene expression of CK1 delta is higher in bladder cancer compared to normal tissue. The purpose of this study is to investigate the role of CK1 delta in the progression of bladder cancer, and the feasibility of CK1 delta as a therapeutic target. Lentiviral delivery of shRNA and CK1 delta inhibitors was used to modulate gene expression or kinase activity of CK1 delta in bladder cancer cell lines. Cell viability, cell cycle progression, apoptosis, migration and downstream signaling pathway were analyzed. The results showed that knocking down CK1 delta or treatment of CK1 delta inhibitors decreased cell viability and inhibited wnt/β-catenin pathway in bladder cancer cell lines. CK1 delta inhibitors increased the accumulation of sub-G1 phase by flow cytometry analysis, as well as the activation of caspase-3, 8, 9 and PARP cleavage by Western blot, indicating the promotion of cell apoptosis. Knocking down of CK1 delta and the treatment of CK1 delta inhibitors impaired cell migration activity, and altered protein expression of EMT markers, such as E-cadherin, vimentin, snail and slug. In conclusion, this study demonstrates that CK1 delta is a potential target for bladder cancer therapy.
Citation Format: Chun-Han Chen. CK1 delta as a therapeutic target in bladder 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 537.
Abstract 5375: Whole-genome sequencing reveals genomic signatures associated with the immunologic microenvironments in Chinese NSCLC patients
Authors: Wang Cheng , Dai Juncheng , Gu Yayun , Hu Zhibin , Shen Hongbing 
Published: August 2018

Abstract
Over the past decades, next-generation sequencing has accelerated the systematic characterization of genomic events, including single base substitutions and small insertions/deletions (indels), and has yielded substantial insights into the unique and shared genomic features of the two NSCLC subtypes. Genomic studies of lung cancer have mainly been conducted in patients from Western countries; however, Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms in addition to smoking. To reveal the underlying mechanisms, we presented a comprehensive genomic landscape of 149 Non-Small Cell Lung Cancer (NSCLC) cases. We identified 15 potential driver genes and three mutational signatures, two of which have been connected with APOBEC enzymes and smoking. In addition, we revealed that Chinese patients are specially characterized by not only highly clustered and functional EGFR mutations but also a mutational signature, that is associated with inflammatory tumor-infiltrating lymphocytes (P = 0.001). The EGFR mutation rate is significantly increased with the proportion of the MS3 signature (P&lt;0.001). As a classic tumor-enabling hallmark, inflammatory infiltration may contribute to the accumulation of EGFR mutations, especially in never-smokers. Additionally, patients with a higher proportion of the MS3 signature carried a higher contribution of characterized chromosomal rearrangements (P&lt;0.001). The results revealed specific genomic features in the inflammatory microenvironments in Chinese patients with potential implications for understanding the etiology, prevention and therapy of NSCLC.
Citation Format: Cheng Wang, Juncheng Dai, Yayun Gu, Zhibin Hu, Hongbing Shen. Whole-genome sequencing reveals genomic signatures associated with the immunologic microenvironments in Chinese NSCLC patients [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 5375.
Abstract 5381: Understanding the genesis and oncogenic consequences of tandem duplicator phenotypes in human cancers
Authors: Menghi Francesca , Barthel Floris , Yadav Vinod , Tang Ming , Ji Bo , Carter Gregory , Jonkers Jos , Verhaak Roel , Scully Ralph , Liu Ed 
Published: August 2018

Abstract
Genome-scale instability configurations in cancer genomes are commonly found across different types of cancers. We and others have described an enrichment of head-to-tail somatic segmental tandem duplications (TDs) in primarily breast and ovarian cancers, a configuration known as the Tandem Duplicator Phenotype (TDP). Here, we perform a meta-analysis of 2,717 human cancer genomes, representing 30 different tumor types and refine the TDP classification based on the identification of highly specific and recurrent TD span profiles. Overall, we identify the TDP as a highly recurrent chromosomal instability configuration, occurring in 14% of the cancer genomes examined. The TDP is remarkably prevalent in triple negative breast cancer (50%), ovarian cancer (55%), and uterine cancers (45%), but is infrequent in most other cancer types. In TDP tumors, TD span sizes can be classified into three major discrete intervals with modal values of 10 Kb, 230 Kb, and 1.7 Mb. TDPs with a dominant TD modal span size of 10 Kb are strongly associated with conjoint TP53 mutations and BRCA1 deficiency across different tumor types. TDPs with larger span sizes (230 Kb and 1.7 Mb) are associated with CCNE1 pathway activation and CRKRS/CDK12 gene disruptions. We proved the driver role of the conjoint abrogation of the BRCA1 and TP53 genes for the induction of TDP cancers with the 10 Kb predominant span peak by generating mammary cancers with a Tandem Duplicator Phenotype of the ~10 Kb TD span configuration type in genetically modified mouse models harboring deleterious mutations in only these same two genes. Lastly, we describe how heterogeneous combinations of tumor suppressors and chromatin topologically associating domains are disrupted, and oncogene and tissue-specific super enhancers are duplicated as a consequence of TD formation in TDP tumors. In summary, our work unifies a number of observations around a specific cancer genomic signature, shows how a number of genetic drivers converge on creating the tandem duplicator phenotype, and how the downstream consequences of the TDs generate oncogenic diversity that allows for further formation of genetic subgroups. The implications of TDP-based stratification for therapy response are currently under investigation.
Citation Format: Francesca Menghi, Floris Barthel, Vinod Yadav, Ming Tang, Bo Ji, Gregory Carter, Jos Jonkers, Roel Verhaak, Ralph Scully, Ed Liu. Understanding the genesis and oncogenic consequences of tandem duplicator phenotypes in human cancers [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 5381.
Abstract 5393: Exosomal microRNA profiles in peritoneal fluids as a therapeutic biomarker for peritoneal metastasis of gastric cancer
Authors: Ohzawa Hideyuki , Kumagai Yuko , Yamaguchi Hironori , Hosoya Yoshinori , Sata Naohiro , Kitayama Joji 
Published: August 2018

Abstract
Background: Repeated intraperitoneal chemotherapy (IPC) using taxane is highly effective for peritoneal metastasis. Peritoneal fluids are supposed to contain various factors derived from tumor cells seeded in peritoneal cavity. This study aimed to explore possible biomarkers for suitable IPC using exosomal miRNA profiles derived from malignant ascites or peritoneal lavages.
Methods: Peritoneal fluid samples were obtained from 11 patients with peritoneal metastasis (PM+) and 14 patients who received gastrectomy for early gastric cancer (PM-). Exosomal fractions were isolated using ultracentrifuge method and total RNAs were extracted. The pooled RNA samples in both groups were mixed and expression of miRNAs were analyzed using miRNome miScript miRNA PCR Array (QIAGEN). Based on these results, we constructed the custom miRNA PCR panel and evaluates expression of miRNAs in individual samples.
Results: The comprehensive PCR analysis showed that total of 56 and 54 miRNAs were strongly expressed in exosomes in PM+ and PM- peritoneal fluid sample, respectively. In analysis of individual samples, 7 upregulated miRNAs (miR-150-5p, miR-223-3p, miR-204-5p, miR-720, and miR-92a, miR-21-5p, miR-4301, and miR-342-3p) and 3 downregulated miRNAs (miR-29a-3p, miR-29b-3p, and miR-29c-3p) were identified in PM+ samples.
Conclusion: In patients who receive IPC, peritoneal fluids can be repeatedly obtained from peritoneal access port. Exosomal miRNA profiles of peritoneal fluid samples might be a useful biomarker to determine the therapeutic efficacy as well as to predict the outcome in those patients with peritoneal metastasis.
Citation Format: Hideyuki Ohzawa, Yuko Kumagai, Hironori Yamaguchi, Yoshinori Hosoya, Naohiro Sata, Joji Kitayama. Exosomal microRNA profiles in peritoneal fluids as a therapeutic biomarker for peritoneal metastasis of 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 5393.