tbuckley/cabot-search huggingface dataset:
Abstract 5359: An ultrasensitive and highly reproducible hybridization capture-based Next-Generation Sequencing clinical assay to enable precision oncology in patients with solid tumors
Authors: Moises Hernandez, Sara King, Sharanya Raghunath, Christopher Johnson, David Loughmiller, Lincoln Nadauld, Pravin J. Mishra
Journal: Cancer Research (2017)

Abstract Sequencing whole cancer exome and whole genome provides useful information to study cancer evolution. However, cost and amount of data may become overwhelming. Enrichment capture-based methods to design custom targeted gene panel have rapidly evolved recently in cancer genomics arena. Custom targeted gene sequencing entails several advantages (i.e., better quality, ethical, affordable, technically suitable, personalized and reimbursable) for cancer patients over whole exome and whole genome sequencing. With this in mind, and to enable precision oncology in patients with solid tumors, we developed ICG100 2.0 panel, a hybridization capture-based next-generation sequencing assay for targeted sequencing of all exons and flanking introns of 162 commonly mutated cancer genes in formalin-fixed, paraffin-embedded (FFPE) tumors. To establish ICG100 2.0 panel, we compared three commercially available capture based technologies and evaluated reproducibility, sensitivity, specificity and the detection limit for low-frequency variants using internally developed bioinformatics pipeline. Cell lines, reference standards/synthetic DNA and solid tumor samples with the known genetic information was utilized in this analysis. Results were derived from MiSeq and NextSeq platforms and cross-compared on other platforms, including MassArray and ddPCR for establishing concordance and uniformity. Intra and interrun replicates were utilized to assess the quality, precision and reproducibility of variant calling. Mean depth of coverage was observed at &amp;gt;300X with &amp;gt;99% sensitivity and specificity. These findings and observations will guide other clinical laboratories to establish new assay that require less DNA input, enzyme based fragmentation and reduced preparation time. While we show that the three capture based methods (after comparison) had an overall accuracy in SNP and CNV detection similar to each other with minor differences, we describe an approach to assess and establish the best assay from the clinical standpoint to guide treatment decisions and match cancer patients to the most appropriate clinical trials. Citation Format: Moises Hernandez, Sara King, Sharanya Raghunath, Christopher Johnson, David Loughmiller, Lincoln Nadauld, Pravin J. Mishra. An ultrasensitive and highly reproducible hybridization capture-based Next-Generation Sequencing clinical assay to enable precision oncology in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5359. doi:10.1158/1538-7445.AM2017-5359
Abstract 1949: Salvage pathway enzyme HPRT as a molecular marker for Burkitt’s Lymphoma
Authors: Michelle H. Townsend, John Ellis Lattin, Michael D. Anderson, Abigail Felsted, Edwin Velazquez, Evita Weagel, Richard Robison, Kim L. O'Neill
Journal: Cancer Research (2017)

Abstract The aim of this study is to investigate the potential of Hypoxanthine phosphoribosyltransferase (HPRT) as a surface biomarker and target for future immunotherapies in Burkitt’s B-cell Lymphoma. B-cell malignancies are the most common type of childhood cancer. Development of immunotherapies could improve current treatment. HPRT is a cytosolic transferase involved in nucleotide production via the purine salvage pathway. Altered expression of TK1, a salvage pathway enzyme, is an indicator of prognosis and diagnosis in multiple cancer types due to active proliferation of cells and the resulting elevated nucleotide demand. It has previously been reported that some salvage pathway enzymes are found on the surface of Burkitt’s Lymphoma cells. HPRT presence on the surface of this B-cell lymphoma subtype could provide a target for adoptive cell transfer and other immunotherapies. The potential surface presentation of HPRT was assessed using flow cytometry, scanning electron microscopy (SEM), and cytoplasmic staining on both healthy lymphocytes and Burkitt’s Lymphoma cells (Raji). Flow cytometry experiments with HPRT antibodies and fluorescent-labeled secondary antibodies show that Raji cells exhibit an 81.4% (p-value .0001) positive fluorescence shift when compared to IgG controls (1.5%). Healthy lymphocytes had a fluorescence shift of 2.38% (p-value .9787). The presence of HPRT on the surface of both Raji cells and healthy lymphocytes was further confirmed using gold-labeled antibodies. Utilizing a scanning electron microscope, the presence of the protein on the surface was evaluated and quantified via increases in gold weight percentage of the sample. When treated with antibodies against HPRT, there was a significant increase in gold binding along with an increase in gold weight percentage. These results suggest a direct relationship between HPRT and the surface of Burkitt’s lymphoma cells, indicating HPRT as a potential target for future immunotherapeutic treatment in Burkitt’s B-cell lymphoma pediatric patients. Citation Format: Michelle H. Townsend, John Ellis Lattin, Michael D. Anderson, Abigail Felsted, Edwin Velazquez, Evita Weagel, Richard Robison, Kim L. O'Neill. Salvage pathway enzyme HPRT as a molecular marker for Burkitt’s Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1949. doi:10.1158/1538-7445.AM2017-1949
Abstract 3776: Examination of ERCC1 status in circulating tumor cells as a prognostic tool for patients with nasopharyngeal carcinoma
Authors: Edwin P. Hui, Brigette BY Ma, KC Allen Chan, Charles ML Chan, SC Cesar Wong, Ka Fai To, Herbert HF Loong, Frankie KF Mo, Roger KC Ngan, Anthony TC Chan
Journal: Cancer Research (2017)

Abstract Investigation of the expression pattern of DNA-repair protein excision repair cross-complementation group 1 (ERCC1) has been reported to allow selection of patients with non-small cell lung cancer who are likely to benefit from cisplatin-based therapy. Recent evidence suggests that ERCC1 expression may also find prognostic use in patients with nasopharyngeal carcinoma (NPC). We evaluated ERCC1 expression and genotype from NPC tissues and peripheral blood mononuclear cells of patients with NPC. ERCC1 expression was detected in 61/77 cases (79.2%) with varying intensities, where high ERCC1 expression significantly associated with worse relapse-free survival (RFS) (HR 2.34, 1.06-5.16, p=0.036). In addition, the presence of ERCC1 C118T genotype was significantly associated with favorable RFS and overall survival (OS) in a subgroup of patients with undetectable post-treatment plasma EBV DNA. These findings support a prognostic role for ERCC1 examination in NPC. However, the invasive nature of obtaining biopsy samples for tumor marker studies is a major hindrance of this approach. To facilitate the investigation of ERCC1 expression in a noninvasive manner, we have developed a negative selection immunomagnetic method for isolating circulating tumor cells from patient blood. Cell line spike-in experiments reveal a mean recovery rate of 66% for NPC cells with greater than 99% removal of non-targeted blood cells. Specificity of CTC identification was confirmed by detection of the expression of the Epstein-Barr virus encoded small RNA (EBER) in the CTCs. This method also allowed the simultaneous analysis of the expression of multiple protein markers including CD45, cytokeratin and ERCC1. It is expected that the development of noninvasive methodologies for tumor marker studies will facilitate their clinical application for improved patient care and monitoring in the future. Note: This abstract was not presented at the meeting. Citation Format: Edwin P. Hui, Brigette BY Ma, KC Allen Chan, Charles ML Chan, SC Cesar Wong, Ka Fai To, Herbert HF Loong, Frankie KF Mo, Roger KC Ngan, Anthony TC Chan. Examination of ERCC1 status in circulating tumor cells as a prognostic tool for patients with nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3776. doi:10.1158/1538-7445.AM2017-3776
Abstract 461: Dichotomous roles of Dicer1 in rhabdomyosarcoma and angiosarcoma
Authors: Jason A. Hanna, Matthew R. Garcia, Catherine J. Drummond, Jonathon C. Go, David Finkelstein, Jerold E. Rehg, Mark E. Hatley
Journal: Cancer Research (2017)

Abstract Pediatric and adult angiosarcomas are rare and highly aggressive soft tissue sarcomas with an extremely poor prognosis. Due to the rarity of this disease especially in children, the molecular drivers and optimized treatment strategies for patients are lacking, highlighting the need for genetic and in vivo animal models. MicroRNAs are a class of small RNAs that regulate gene expression and are often dysregulated in cancers including sarcomas. DICER1 is required for microRNA biogenesis and germline DICER1 mutations result in a cancer predisposition syndrome associated with increased risk of benign and malignant tumors including rhabdomyosarcoma (RMS), a pediatric soft tissue sarcoma resembling developmentally arrested skeletal muscle. Here we show Dicer1 expression is required for tumorigenesis in a mouse model of RMS driven by activation of oncogenic Smoothened by Cre recombinase expressed from the adipose protein 2 (aP2) promoter (aP2-Cre). Unexpectedly, in studying the role of Dicer1 in RMS, we found that Dicer1 deletion with aP2-Cre leads to aggressive angiosarcoma. Angiosarcoma development was independent of the Smoothened oncogene and other genetically engineered oncogenes or tumor suppressor loss, providing the first in vivo mouse model of biallelic Dicer1 loss alone driving tumorigenesis. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma and were enriched for microRNA-23 target genes including the oncogene Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis. The aP2-Cre;Dicer1Flox/- model provides a simple in vivo animal model to study angiosarcoma for novel therapeutics and the molecular mechanisms of cancer initiation, progression, and metastasis. In addition, our results demonstrate DICER1 and microRNAs play major and opposing roles in sarcomagenesis. Citation Format: Jason A. Hanna, Matthew R. Garcia, Catherine J. Drummond, Jonathon C. Go, David Finkelstein, Jerold E. Rehg, Mark E. Hatley. Dichotomous roles of Dicer1 in rhabdomyosarcoma and angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 461. doi:10.1158/1538-7445.AM2017-461
Abstract 4373: SOX2-related gene signature predicting the prognosis in head and neck squamous cell cancer
Authors: Young-Gyu Eun, Young Chan Lee, Jun Eul Hwang
Journal: Cancer Research (2017)

Abstract Purpose: Numerous studies have indicated that Sex-determining region Y-box 2 (SOX2) is involved in many squamous cell carcinomas. However, the role of SOX2 in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, we investigated whether activation of SOX2 is significantly associated with prognosis in HNSCC. Methods: Gene expression signature reflecting SOX2 activation was identified in HNSCC cohort, and patients were stratified into two groups according to this signature: SOX2-high group or SOX2-low group. Validation of the signature was sought in two independent patient groups. The association between the signature and prognosis of patients was assessed. Results: The SOX2-low group was associated with poor prognosis for HNSCC in three independent patient cohorts. In a multivariate analysis, the impact of the SOX2 signature on overall survival (OS) was independent of other clinical variables [hazard ratio (HR), 1.45; 95% confidence interval (CI), 1.09 - 1.92; P=0.01]. In patients who received radiotherapy (RT), SOX2-low group had significantly poor OS than those in SOX2-high group. Conclusions: SOX2-low signature is associated with poor prognosis in patients with HNSCC and could be used to predict patients who would benefit from RT. Note: This abstract was not presented at the meeting. Citation Format: Young-Gyu Eun, Young Chan Lee, Jun Eul Hwang. SOX2-related gene signature predicting the prognosis in head and neck squamous cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4373. doi:10.1158/1538-7445.AM2017-4373
Abstract 4685: Immune checkpoint protein VISTA is a critical regulator of the IL-23/IL-17 inflammatory axis
Authors: Na Li, Wenwen Xu, Ying Yuan, Natarajan Ayithan, Yasutomo Imai, Xuesong Wu, Halli Miller, Michael Olson, Samuel T. Hwang, Subramaniam Malarkannan, Li Wang
Journal: Cancer Research (2017)

Abstract V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4+ and CD8+ T cell activation when expressed on antigen-presenting cells. Vsir-/- mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir-/- CD4+ and CD8+ T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity has not been demonstrated. Our current study shows that VISTA-blocking monoclonal antibody (mAb) enhanced anti-tumor T cell response, and synergized with a peptide vaccine and TLR7 agonist imiquimod as adjuvant to suppress tumor growth in the B16 melanoma model. Surprisingly, the therapeutic effect of this combination therapy was abolished in the IL17R knockout hosts, indicating that the IL-17-mediated inflammation is regulated by VISTA and is required for anti-tumor immunity in the context of VISTA blockade. To better define the regulatory role of VISTA in inflammation, we employed a murine model of psoriasis induced by topical treatment of IMQ. Our data show that VISTA deficiency exacerbated the psoriasiform inflammation. Enhanced TLR7 signaling in Vsir-/- dendritic cells (DCs) led to the hyper-activation of Erk1/2 signaling and augmented the production of IL-23. IL-23, in turn, promoted the expression of IL-17A in both TCRgd+ T cells and CD4+ Th17 cells. Furthermore, VISTA regulates the peripheral homeostasis of CD27- gd T cells, and their activation upon TCR-mediated or cytokine-mediated stimulation. IL-17A-producing CD27- gd T cells were expanded in the Vsir-/- mice and amplified the inflammatory cascade. Together, these results indicate that VISTA is a critical regulator of the IL-23/IL-17-mediated inflammatory axis. Ongoing studies will define how IL-17 regulates tumor-reactive immunity in the context of VISTA blockade and TLR vaccine adjuvant. Citation Format: Na Li, Wenwen Xu, Ying Yuan, Natarajan Ayithan, Yasutomo Imai, Xuesong Wu, Halli Miller, Michael Olson, Samuel T. Hwang, Subramaniam Malarkannan, Li Wang. Immune checkpoint protein VISTA is a critical regulator of the IL-23/IL-17 inflammatory axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4685. doi:10.1158/1538-7445.AM2017-4685
Abstract LB-289: Computational detection of oncogene-centric pathway members
Authors: Joshua Broyde, David Simpson, Diana Murray, Alexander Lachmann, Federico M. Giorgi, Barry Honig, Alejandro E. Sweet-Cordero, Andrea Califano
Journal: Cancer Research (2017)

Abstract Elucidation of the full complement of members of oncogenic signaling pathways is critical for understanding dysregulated function in cancers. Our knowledge of experimentally verified human gene-regulatory networks and protein-protein interactions remains incomplete, thus limiting their use for predicting novel members of these critical pathways. We present a method that uses a machine learning approach to predict novel members of these aberrantly activated or inactivated pathways. We integrate predictions of protein-protein interactions, gene regulatory networks, post-translational modifications and co-segregation of mutational status and protein activity. This approach produces novel predictions for these pathways. For the Kras and EGFR pathway, these predictions are highly enriched for genes known to by synthetic lethal for these two pathways. Knockdown of top candidates derived from this approach decreased growth in a Kras-activated context, indicating their importance in Kras regulated pathways. Citation Format: Joshua Broyde, David Simpson, Diana Murray, Alexander Lachmann, Federico M. Giorgi, Barry Honig, Alejandro E. Sweet-Cordero, Andrea Califano. Computational detection of oncogene-centric pathway members [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-289. doi:10.1158/1538-7445.AM2017-LB-289
Abstract 253: Mammary tumorigenesis causes bone loss and dietary selenium supplementation does not affect such bone loss in male MMTV-PyMT mice
Authors: Lin Yan
Journal: Cancer Research (2017)

Abstract Cancer progression is accompanied by wasting that eventually results in cachexia characterized by significant weight loss and multi-organ functional failures. Limited clinical trials indicate that bone is adversely affected by cancer-associated wasting. To determine the effects of breast cancer on skeletal health, we performed micro-computed tomographic analysis of femurs and vertebrae collected from a recently completed study showing that dietary supplementation with selenium (methylseleninic acid, 2.5 mg Se/kg) reduced male mammary tumorigenesis in MMTV-PyMT mice. Compared to age-matched non-tumor-bearing mice (MMTV-PyMT negative), the presence of mammary tumors significantly reduced bone volume fraction, trabecular thickness and bone mineral density and increased the structure model index (an indicator of the plate- and rod-like geometry of trabecular structure) in femoral trabecular bone. Mammary tumor development did not affect vertebral trabeculae nor femoral and vertebral cortical bone, except it significantly reduced cortical bone thickness of vertebrae. There were no differences in aforementioned measurements between groups with or without selenium supplementation. In conclusion, mammary tumorigenesis causes bone loss and dietary selenium supplementation at 2.5 mg Se/kg, which is antitumorigenic, does not affect mammary tumor-associated bone loss in this male MMTV-PyMT breast cancer model. Citation Format: Lin Yan. Mammary tumorigenesis causes bone loss and dietary selenium supplementation does not affect such bone loss in male MMTV-PyMT mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 253. doi:10.1158/1538-7445.AM2017-253
Abstract 2752: Liquid biopsy analysis of FGFR3 and PIK3CA hotspot mutations for disease surveillance in bladder cancer
Authors: Emil Christensen, Karin Birkenkamp-Demtröder, Iver Nordentoft, Søren Høyer, Kirstin Van Der Keur, Kim Van Kessel, Ellen Zwarthoff, Mads Agerbæk, Torben Falck Ørntoft, Jørgen Bjerggaard Jensen, Lars Dyrskjøt
Journal: Cancer Research (2017)

Abstract Background: Disease surveillance in patients with bladder cancer is important for early diagnosis of progression and metastasis and for optimal therapeutic treatment. Experimental procedures: Droplet digital PCR (ddPCR) assays were developed and tumour DNA from two patient cohorts was screened for FGFR3 and PIK3CA hotspot mutations. One cohort (NMIBC cohort) included 363 patients with non-muscle invasive bladder cancer (NMIBC). Another cohort (Cx cohort) included 468 patients with bladder cancer undergoing radical cystectomy. Urine supernatants (NMIBC cohort: n=216, Cx cohort: n=27) and plasma samples (NMIBC cohort: n=39, Cx cohort: n=27) from patients harbouring mutations were subsequently screened using ddPCR assays. Liquid biopsies were collected from 2003-2015 with up to 11.3 years of follow-up for the NMIBC cohort and from 1995-2009 with up to 13.5 years of follow-up for the Cx cohort. Results and limitations: In total, 36% of the patients in the NMIBC cohort (129/363) and 11% of the patients in the Cx cohort (44/403) harboured at least one hotspot mutation in FGFR3 or PIK3CA. Screening of DNA from serial urine supernatants from the NMIBC cohort showed high levels of tumour DNA (tDNA) to be significantly associated with later disease progression (p=0.003). Furthermore, high levels of tDNA in preoperative urine supernatants and plasma samples were associated with recurrence in the Cx cohort (p=0.068 and p=0.016 respectively). A positive correlation between the levels of tDNA in urine and plasma was observed (corr.=0.6). The retrospective study design and the low volumes of plasma available for analysis were limitations of the study. Conclusions: Increased levels of FGFR3 and PIK3CA mutated DNA in urine and plasma is indicative of later progression and metastasis in bladder cancer. Citation Format: Emil Christensen, Karin Birkenkamp-Demtröder, Iver Nordentoft, Søren Høyer, Kirstin Van Der Keur, Kim Van Kessel, Ellen Zwarthoff, Mads Agerbæk, Torben Falck Ørntoft, Jørgen Bjerggaard Jensen, Lars Dyrskjøt. Liquid biopsy analysis of FGFR3 and PIK3CA hotspot mutations for disease surveillance in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2017-2752