bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1182: Exploring longitudinal intra-tumor heterogeneity in cancer using whole genome sequencing and RNA rescue
Authors: Parulkar Rahul , Benz Steve , Vaske Charlie , Radenbaugh Amie , Szeto Christopher 
Published: August 2018

Abstract
We present a methodology for confidently characterizing subclonal exonic variants by pairing whole genome sequencing (WGS) with transcriptomics (RNAseq). We demonstrate the utility of this method by studying subclonal population changes in longitudinally collected samples.
Detection of variants specific to minority subclones has ordinarily only been achievable with very high-depth sequencing obtained by whole exome (WES) or targeted sequencing, and most available tools for studying subclonality require WES data as input. Although WGS provides more coverage breadth than WES, identifying subclonal mutations by WGS alone is difficult due to reduced read support for each variant. Detecting minority variants in WGS data is made especially difficult when tumor purity is low and subclonality is high. RNAseq is typically performed at high-depth and may be useful for replacing WES in detecting subclonal variants.
Our method has two steps: 1) Use WGS to establish a low-confidence preliminary set of variants present in the tumor, and 2) bolster the confidence in those variants by observing whether the variants are expressed in the RNAseq. We used this methodology to generate WES-like data from WGS+RNAseq in simulated data, and show that we can correctly identify subclonal populations using publicly available tools designed for WES data. Additionally, we demonstrate using this method to characterize the evolutionary lineage of the tumor population in a patient who was biopsied multiple times throughout several treatments, for whom only WGS and RNAseq data is available. Our proposed method resulted in 60% more confident variants than its WGS-only counterpart.
As tumor tissue availability is low and cost of sequencing is substantial, the choice of which molecular characterizations to perform is difficult. Here we show that paired WGS and RNAseq can be leveraged to infer information typically only obtained from WES, in addition to providing intergenic and expression information.
Citation Format: Rahul Parulkar, Steve Benz, Charlie Vaske, Amie Radenbaugh, Christopher Szeto. Exploring longitudinal intra-tumor heterogeneity in cancer using whole genome sequencing and RNA rescue [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 1182.
Abstract 119: Immunotherapy with dendritic cells inhibited tumor growth on an ID8 orthotropic mouse model of ovarian cancer
Authors: Kim Min-Je , Kim Joo-won , Kim Ju-hyun , Lee Young-Jae , Lee Shin-Wha , Kim Yong-Man 
Published: August 2018

Abstract
Background and Purpose: Ovarian cancer is the most frequent cause of death from gynecologic malignancy. Recently, immunotherapies have been suggested as ways to treat this malignancy. However, the ideal of immunotherapy has not been realized yet in ovarian cancer patients. Therefore, we investigated effects of monocyte-derived dendritic cells (mono DCs) and new-generation DCs subset (new DCs) on an ID8 orthotropic mouse model of ovarian cancer.
Methods: Mono DCs were prepared from bone marrow of C57BL/6 mice. We isolated monocyte from bone marrow by monocyte isolation kit. Isolated monocyte was incubated for 7 days with IL-4 and GM-CSF. In addition, monocytes were pulsed with LPS and ID8 tumor lysate while incubating. Likewise new DCs were isolated from bone marrow of C57BL/6 mice. We isolated lineage negative cells from bone marrow using lineage cell depletion kit. Isolated cells were incubated with IL-4 and GM-CSF; also the cells were pulsed by ID8 tumor lysate and Rg3, which is a ginsenoside. Orthotropic model of ID8 was made on C57BL/6 mice. We injected 5x106 cells into peritoneal cavity. 4 weeks after cell injection, mice were grouped into three groups, which were vehicle, mono DCs and new DCs. Mice were injected with mono DCs and new DCs. 5x106 cells of DCs were injected 1 time/week for three weeks. One week later, mice were sacrificed and organs were harvested such as peritoneum, phren, ovary and tumor mass for histologic analysis.
Results: DCs treated groups showed lower ascites formation than vehicle group. Ascites were fewest in new DCs group. Survival rate was lowest in vehicle group. Each survival rate is 0% in vehicle, 63% in new DCs and 80% in mono DCs. Also tumor growth at ovary was more decreased in mono DCs and new DCs group. In addition, mono DCs-treated mice showed low level of metastasis to other organs.
Conclusion: Immunotherapy with dendritic cells showed inhibition of tumor growth and metastasis on mouse ovarian cancer. These results indicated that DCs treatments are able to be a potential therapy for ovarian cancer. It also could have synergy with the combined treatment of existing anticancer drugs. However, there are several limitations such as a relatively high dose of DCs and the procedure of isolating DCs needed large amount of bone marrow. We will continue to study and improve these issues.
Citation Format: Min-Je Kim, Joo-won Kim, Ju-hyun Kim, Young-Jae Lee, Shin-Wha Lee, Yong-Man Kim. Immunotherapy with dendritic cells inhibited tumor growth on an ID8 orthotropic mouse model of ovarian 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 119.
Abstract 120: Local immune cytolytic activity stratifies clinical outcome and is linked to the immune microenvironment in breast cancer
Authors: Kawaguchi Tstutomu , Qi Qianya , Peng Xuan , McDonald Kerry-Ann , Narayanan Sumana , Young Jessica , Liu Song , Yan Li , Takabe Kazuaki 
Published: August 2018

Abstract
Purpose: Although a recent genomic landscape study identified molecular and genetic signatures of immune cytolytic activity (CYT) related to immune-mediated cancer elimination, less is known about the clinical relevance of CYT in the tumors linked to immune microenvironment in breast cancer. The aim of our study was to assess whether intratumor CYT associates with genetic alterations and tumor immune microenvironment, which impacts survival in breast cancer patients.
Experimental Design: We utilized genomic data from primary samples of 1,090 breast cancer patients with clinicopathologic information from The Cancer Genome Atlas (TCGA). We developed an immunogenomics pipeline that correlates CYT with clinical outcome and intratumor immune microenvironment, including infiltrating immune cell composition.
Results: Breast cancer displays a range of intratumor CYT. Patients with high CYT showed significantly better prognostic outcome, independent of age, hormonal status, and stage. CYT also has a strongly positive association with the expression of immune checkpoint genes such as PD1, PD-L1, and CTLA4, as well as regulatory T-cell (Treg) markers such as FOXP3 and CCR4. Enrichment of immune-response gene sets was observed in the high-CYT tumors. CYT was associated with higher composition of immune-elimination cells such as CD8+ T-cell, CD4+ T-cell, gamma delta T-cell, and M1 macrophage, as opposed to negatively associated with immunosuppressive cells, such as Treg and M2 macrophage. High CYT was also associated with improved survival in tumor-infiltrating lymphocyte (TIL)-positive breast cancer.
Conclusions: Patients with high CYT breast cancers show improved survival, likely due to high intratumor immunogenicity. CYT could also be used as a potential biomarker for immunologic response within tumors.
Citation Format: Tstutomu Kawaguchi, Qianya Qi, Xuan Peng, Kerry-Ann McDonald, Sumana Narayanan, Jessica Young, Song Liu, Li Yan, Kazuaki Takabe. Local immune cytolytic activity stratifies clinical outcome and is linked to the immune microenvironment 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 120.
Abstract 1205: Long-term survival of children with acute lymphoblastic leukemia, according to treatment regimen, in a regional French population
Authors: Gauthier Sophie , Mounier Morgane , Girard Stéphanie , Briandet Claire , Carli Paule Marie , Maynadie Marc 
Published: August 2018

Abstract
Acute Lymphoblastic Leukemia (ALL) is the main neoplastic disease in children. Treatment is based on chemotherapy associated or not to bone marrow transplantation. The 5-year survival rate in European children is reported as 86% but long term survival data are not available. We investigated the 20 year Overall Survival (OS) and Net survival (NS) of the patients diagnosed in the population of the Côte d'Or area in France. 162 cases were diagnosed in the population of the Côte d'Or area between 1970 and 2015. Cases diagnosed between 1970 and 1979 (n=29) were not formally registered in the registry database but data were available through the unique regional, reference hematology laboratory. All cases were followed until 01 01 2017. The treatment regimens that were used were as follows in chronological order (from the earliest to the most recent); LAL 76 and 80; the FRALLE 83, 87 and 89 until 1993; the FRALLE 93 from 1993 to 2001 and then the FRALLE 2000. The 20-y OS and NS of ALL was respectively 66% and 67%. It was 59% in boys but 75% in girls (p=0.04). No statistical difference was found according to age. According to lineage subtype, the 20-y NS was 82% in B-ALL, 65% in T-ALL and 34% in ALL, not otherwise specified (p&lt;0.001). According to treatment regimen, the 20-y-NS was 51% before the use of the FRALLE 93, compared to 71% for cases treated by the FRALLE 93 regimen and 95% for those treated with the FRALLE 2000 regimen (p&lt;0.001). The survival was 95% irrespective of the time of diagnosis following introduction of the FRALLE 2000 regimen. Data on long term survival of ALL in children are scarce. Our results show 1) a very high 20 year survival rate indicating the efficacy and safety of the treatment regimens used, 2) the utility of randomized clinical trials to define new standards of care.
Citation Format: Sophie Gauthier, Morgane Mounier, Stéphanie Girard, Claire Briandet, Paule Marie Carli, Marc Maynadie. Long-term survival of children with acute lymphoblastic leukemia, according to treatment regimen, in a regional French population [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 1205.
Abstract 1221: Chronic lymphocytic leukemia risk variants are associated with alteration of epigenetic states in regulatory regions
Authors: Yan Huihuang , Tian Shulan , Kleinstern Geffen , Slager Susan 
Published: August 2018

Abstract
Chronic lymphocytic leukemia risk variants are associated with alteration of epigenetic state in regulatory regions The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWASs) reside in noncoding genomic regions. Functional impact of noncoding casual variants on target gene expression often involves regulatory mechanisms, typically through altering local chromatin accessibility, histone modifications, transcription factor (TF) binding affinity and chromatin interactions. In chronic lymphocytic leukemia (CLL), we and others have identified 41 GWAS risk variants, whose mechanism of action in CLL etiology remains largely unknown. In this study, we aim to decipher the regulatory potential of these variants and to better understand the mechanisms contributing to dysregulation of genes implicated in CLL pathogenesis. We performed ChIP-seq for H3K4me3, H3K4me1, H3K27ac and H3K27me3 in CLL. In addition, we also analyzed over 250 public ChIP-seq, ATAC-seq, DNase-seq, FAIRE-seq, and chromatin interaction data in CLL, B cells and/or lymphoblastoid cell lines. Comparing the 41 index SNPs and the nearby SNPs they associated with in linkage disequilibrium (R2 at least 0.5 in the EUR ethnic group in 1000 Genomes Project) to the above epigenetic data sets revealed overlaps with regulatory regions in 38 of the risk loci, with 28 of the loci overlapping super-enhancers. We used two approaches to elucidate the mechanisms of potential SNP causality. First, we used GATK UnifiedGenotyper to infer genotype for the SNPs that overlapped open chromatin regions and ChIP-seq peaks, by which evidence of imbalance between reference and alternative allele was identified at heterozygous sites. Second, for SNPs located within open chromatin regions or ChIP-seq peaks, we used FIMO program to scan the 100bp sequences centered on the SNPs for significant matches (p=1e-05) to the position weight matrices in five TF binding motif databases; SNPs that had TF motifs altered by the alternative alleles were retained. Together, these two approaches revealed evidence for allele imbalance or TF binding motif alterations at 36 of the 38 CLL risk loci, suggesting the generality of epigenetic regulation in CLL pathogenesis. Further analysis of chromatin interaction, gene expression and expression quantitative trait loci data will likely link the casual SNPs to their target genes.
Citation Format: Huihuang Yan, Shulan Tian, Geffen Kleinstern, Susan Slager. Chronic lymphocytic leukemia risk variants are associated with alteration of epigenetic states in regulatory regions [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 1221.
Abstract 1223: Significance of GSTM1 and GSTT1 gene polymorphism to breast cancer susceptibility in Nigerian women
Authors: Ogunlana Olubanke O. , Ortiseweyinmi Omaghomi , Ajoke Sadiq , Fatiregun Omolara , Rotimi Solomon O. , Adegboye Bose E. , Iweala Emeka E. , Igbinoba-Adebayo Angie O. 
Published: August 2018

Abstract
Human glutathione-S-transferases play a key role in the metabolism of drugs and environmental chemicals. There have been conflicting reports on the association of breast cancer susceptibility with null genotypes of glutathione-S-transferase (GST) classes of mu and theta (GSTM1 and GSTT1). However, this is the first report of the association of null genotypes of GSTs with breast cancer patients from Nigerian population. By multiplex PCR, we examined the null genotypes of GSTM1 and GSTT1 in relation to breast cancer risk in Nigerian women. The case-control study included 56 clinically diagnosed breast cancer patients and age-matched control participants. Odds ratio (OR) and 95% confidence interval (Cl) from conditional logistic regression model were used to estimate the association between GSTM1 and GSTT1 subtypes and breast cancer risk. The frequencies of GSTM1 and GSTT1 null genotypes in breast cancer (BC) patients differed from healthy controls (HC) (61% in BC vs. 39% in HC and 66% in BC vs. 34% in HC for GSTM1 and GSTT1 respectively). GSTM1 and GSTT1 null genotypes and their combinations were associated with increased breast cancer risk [OR = 3.06 (95% Cl 0.98-9.48)], [OR = 14.06 (95% Cl 3.02-70.6)] and [OR = 6.98 (95% Cl = 0.11-16.5)] respectively. The study showed an increased breast cancer risk in patients with GSTT1 homozygous gene deletions with relative risk (RR) value of 5.6 than those with GSTM1 (RR = 1.77). In conclusion, the data from our work provide evidence of increased risk of breast cancer associated with GSTM1 and GSTT1 homozygous gene deletions in women from Nigeria.
Citation Format: Olubanke O. Ogunlana, Omaghomi Ortiseweyinmi, Sadiq Ajoke, Omolara Fatiregun, Solomon O. Rotimi, Bose E. Adegboye, Emeka E. Iweala, Angie O. Igbinoba-Adebayo. Significance of GSTM1 and GSTT1 gene polymorphism to breast cancer susceptibility in Nigerian women [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 1223.
Abstract 1233: Reducing sequence artifact in clinical sequencing of treatment-naïve NSCLC patient using molecular barcoding system
Authors: Namba Kei , Tomida Shuta , Takahashi Yuta , Kurihara Eisuke , Ogoshi Yusuke , Yosioka Takahiro , Torigoe Hidejiro , Sato Hiroki , Shien Kazuhiko , Yamamoto Hiromasa , Soh Junichi , Toyooka Shinichi 
Published: August 2018

Abstract
Background: Recently the clinical significance of compound mutations in cancer relapse and/or acquired resistance has been reported. Amplicon-based deep sequence enables analysis of tiny amount of input DNA, however, a major problem of these high-throughput DNA sequencing is the high rate (~1%) of errors causing potential sequence artifact. Molecular barcoding system, which has been developed to reduce sequencing artifacts as well as to improve mutation detection accuracy, was applied to analyze the frequency of compound EGFR mutations in early stage non-small-cell lung cancer (NSCLC) patients who undergo surgical resection without any presurgical treatment is less described.
Materials and Methods: From 590 consecutive patients, 64 adenocarcinoma cases who underwent surgical resection for primary lung cancer were analyzed by using amplicon-based targeted sequencing method incorporating molecular barcodes in order to detect genetic alterations of 47 genes including EGFR.
Results: Out of 64 samples, EGFR common mutation profiles of 63 (98.4%) by molecular-barcode sequencing corresponded to those by clinical test. Uncommon EGFR mutations were detected in 7 cases (10.9%). Among the three types of EGFR major mutation, G719X (60%, 3/5) showed a significantly higher incidence of EGFR double mutations than L858R (9.5%, 4/42) or Ex19del (0%, 0/17) (p = 0.0052). Co-mutations of other genes were observed in 20 EGFR-mutated cases. TP53 mutations were frequently detected in younger age (p = 0.0066) and pStage II-III cases (p = 0.042).
Conclusion: Amplicon sequencing incorporating molecular barcoding system is a feasible approach to characterize predictive or prognostic mutations in early stage treatment naïve NSCLC patients, revealing those case who harbor EGFR G719X mutation have a significantly higher incidence of EGFR double mutations, likely to have worse prognosis.
Citation Format: Kei Namba, Shuta Tomida, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Takahiro Yosioka, Hidejiro Torigoe, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka. Reducing sequence artifact in clinical sequencing of treatment-naïve NSCLC patient using molecular barcoding 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 1233.
Abstract 1245: Identification of germline variants in cancer susceptibility genes in patients with hereditary breast and ovarian cancer syndrome by massive parallel sequencing in Argentinean population
Authors: Franco Alejandra , Orti Fernando , Perdomo Sandra , Riggi Cecilia , Frecha Cecilia , Oliver Javier 
Published: August 2018

Abstract
Breast cancer is the most frequent cancer and ovarian cancer the seventh most frequent cancer among females worldwide, representing approximately 25% and 4% of all cancers. In Argentina, breast cancer and Ovarian cancer cause 6163 and 1332 deaths per year, respectively. Both breast and ovarian cancers are heterogeneous diseases composed of different tumor types with distinctive features and behaviors. The main risk factors for breast and ovarian cancer include age, family history, and genetics.The genetic components of both of the diseases have been well established, contributing to up to 10% of all breast cancer cases and 15% of all ovarian cancer cases.The two major susceptibility genes for both diseases are BRCA1 and BRCA2, and several other susceptibility genes have been identified. However, in the majority of high-risk breast and/or ovarian cancer (HBOC) families, the genetic predisposition factors remain unidentified, making the genetic counseling of these families challenging. The aim of the current study is to utilize an NGS approach to identify genetic factors that predispose individuals to hereditary breast and/or ovarian cancer (HBOC) in the high-risk Argentinian BRCA1/2 mutation-negative HBOC patients.16 patients were analyzed, the DNA was extracted from a blood samples and was subjected to a targeted massively parallel sequencing platform comprising 141 cancer predisposition genes. We detected in these patient 6 pathogenic variants in SBDS, FANCA, MC1R, WRN, MSR1 and SDHD genes. The effect of these variants are of type: non-synonymous (67%) and stop codon gains (33%). We also found 6 variants of uncertain significance (VUS) in APC, RAD50, SDHB, FANCD2, MLH1 and CDH1 genes.In conclusion, the identification of new variants could help to discover new genes associated to HBOC in the population of Argentina.These findings provide an excellent premise for further studies and could be utilized in the design of more efficient clinical management strategies for HBOC.
Citation Format: Alejandra Franco, Fernando Orti, Sandra Perdomo, Cecilia Riggi, Cecilia Frecha, Javier Oliver. Identification of germline variants in cancer susceptibility genes in patients with hereditary breast and ovarian cancer syndrome by massive parallel sequencing in Argentinean population [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 1245.
Abstract 1256: Lynch syndrome premalignancy upregulates immune checkpoints independently from neoantigen and mutational rates
Authors: Chang Kyle 
Published: August 2018

Abstract
Colorectal carcinomas in Lynch syndrome (LS) patients arise in a background of mismatch repair deficiency that leads to the accumulation of high numbers of mutations and neoantigens, thus causing infiltration by abundant tumor-infiltrating lymphocytes, a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a knowledge gap with regards to the level of immune activation and the assessment of mutation and neoantigen rates in LS premalignancy. We performed whole transcriptomic analysis using next-generation sequencing in a total of 28 colorectal polyps (26 tubular adenomas and 2 hyperplastic polyps) from 21 patients diagnosed with LS (n=11) and FAP (n=10) as comparators and a model of mismatch repair proficient colorectal premalignancy.Overall, LS polyps presented with low mutational and neoantigen rates but displayed a strinking immune activation profile characterized by CD4 T-cells, proinflammatory (TNF, IL12) and checkpoint molecules (LAG-3 and PD-L1). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were secondary to accumulation of indels enriched for deregulation of DNA damage repair pathways (ATM and BRCA1 signaling). Our findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in Lynch syndrome.
Citation Format: Kyle Chang. Lynch syndrome premalignancy upregulates immune checkpoints independently from neoantigen and mutational rates [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 1256.