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Publication Tumor potentiating mechanisms of Fusobacterium nucleatum, a multifaceted microbe.
by Stephanie McInnis published Feb 21, 2017
Commentary refers to: Yongzhi Yang, Wenhao Weng, et al., Fusobacterium nucleatum Increases Proliferation of Colorectal Cancer Cells and Tumor Development in Mice by Activating Toll-Like Receptor 4 Signaling to Nuclear Factor−κ, Up-Regulating Expression of MicroRNA-21 Gastroenterology, Available online 19 November 2016,
Located in Platforms / Scientific Publications
Publication chemical/x-cerius CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer.
by Stephanie McInnis published Feb 21, 2017
CIViC is an expert-crowdsourced knowledgebase for Clinical Interpretation of Variants in Cancer describing the therapeutic, prognostic, diagnostic and predisposing relevance of inherited and somatic variants of all types. CIViC is committed to open-source code, open-access content, public application programming interfaces (APIs) and provenance of supporting evidence to allow for the transparent creation of current and accurate variant interpretations for use in cancer precision medicine.
Located in Platforms / Scientific Publications
Publication chemical/x-cerius Non-Genomic Actions of the Androgen Receptor in Prostate Cancer.
by Stephanie McInnis published Feb 21, 2017
Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens. In the canonical pathway, binding of androgen to AR LBD triggers the release of AR from molecular chaperones which enable conformational changes and protein-protein interactions to facilitate its nuclear translocation where it regulates the expression of target genes. However, preceding AR function in the nucleus, initial binding of androgen to AR LBD in the cytoplasm may already initiate signal transduction pathways to modulate cellular proliferation and migration. In this article, we review the significance of signal transduction pathways activated by rapid, non-genomic signaling of the AR during the progression to metastatic CRPC and put into perspective the implications for current and novel therapies that target different domains of AR.
Located in Platforms / Scientific Publications
Publication Mathematica Notebook Genetic Polymorphism at BCL2 as a predictor for R-CHOP efficacy in patients with diffuse large B-cell lymphoma.
by Stephanie McInnis published Feb 21, 2017
In this study, we examine the usefulness of germline BCL2 singlenucleotide polymorphisms (SNP) in identifying low and high risk patients. Our initial study identified two constitutional BCL2 SNPs significantly associated with survival of DLBCL patients treated with R-CHOP. We independently examined the impact of both SNPs in an independent replication set and the association with survival for one of the SNPs, rs7226979, was confirmed. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid neoplasm and accounts for about 30-40% of non-Hodgkin lymphomas. The prognosis of patients with DLBCL has improved for all ages and both sexes in recent years. One of the reasons for this survival improvement is the addition of rituximab to conventional CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. From March 1, 2001, the British Columbia (BC) Cancer Agency implemented this approach by recommending the combination of CHOP and rituximab (R-CHOP) for all newly diagnosed patients with DLBCL, regardless of age, in the province of BC .
Located in Platforms / Scientific Publications
Publication Mathematica Notebook Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma.
by Stephanie McInnis published Feb 21, 2017
We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.
Located in Platforms / Scientific Publications
Publication Octet Stream Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.
by Stephanie McInnis published Feb 21, 2017
Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10(-13)), 1q42.13 (rs41271473, P=1.06 × 10(-10)), 4q24 (rs71597109, P=1.37 × 10(-10)), 4q35.1 (rs57214277, P=3.69 × 10(-8)), 6p21.31 (rs3800461, P=1.97 × 10(-8)), 11q23.2 (rs61904987, P=2.64 × 10(-11)), 18q21.1 (rs1036935, P=3.27 × 10(-8)), 19p13.3 (rs7254272, P=4.67 × 10(-8)) and 22q13.33 (rs140522, P=2.70 × 10(-9)). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.
Located in Platforms / Scientific Publications
Publication backup file Lipid and Alzheimer's disease genes associated with healthy aging and longevity in healthy oldest-old.
by Stephanie McInnis published Feb 21, 2017
Several studies have found that long-lived individuals do not appear to carry lower numbers of common disease-associated variants than ordinary people; it has been hypothesized that they may instead carry protective variants. An intriguing type of protective variant is buffering variants that protect against variants that have deleterious effects. We genotyped 18 variants in 15 genes related to longevity or healthy aging that had been previously reported as having a gene-gene interaction or buffering effect. We compared a group of 446 healthy oldest-old 'Super-Seniors' (individuals 85 or older who have never been diagnosed with cancer, cardiovascular disease, dementia, diabetes or major pulmonary disease) to 421 random population-based midlife controls. Cases and controls were of European ancestry. Association tests of individual SNPs showed that Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele. Interactions between APOE/FOXO3, APOE/CRYL1, and LPA/CRYL1 did not remain significant after multiple testing correction. In a network analysis of the candidate genes, lipid and cholesterol metabolism was a common theme. APOE, HP, and CRYL1 have all been associated with Alzheimer's Disease, the pathology of which involves lipid and cholesterol pathways. Age-related changes in lipid and cholesterol maintenance, particularly in the brain, may be central to healthy aging and longevity.
Located in Platforms / Scientific Publications
Publication Kollector: transcript-informed, targeted de novo assembly of gene loci.
by Stephanie McInnis published Feb 21, 2017
Motivation: Despite considerable advancements in sequencing and computing technologies, de novo assembly of whole eukaryotic genomes is still a time-consuming task that requires a significant amount of computational resources and expertise. A targeted assembly approach to perform local assembly of sequences of interest remains a valuable option for some applications. This is especially true for gene-centric assemblies, whose resulting sequence can be readily utilized for more focused biological research. Here we describe Kollector, an alignment-free targeted assembly pipeline that uses thousands of transcript sequences concurrently to inform the localized assembly of corresponding gene loci. Kollector robustly reconstructs introns and novel sequences within these loci, and scales well to large genomes – properties that makes it especially useful for researchers working on non-model eukaryotic organisms. Results: We demonstrate the performance of Kollector for assembling complete or near-complete Caenorhabditis elegans and Homo sapiens gene loci from their respective, input transcripts. In a time- and memory-efficient manner, the Kollector pipeline successfully reconstructs respectively 99% and 80% (compared to 86% and 73% with standard de novo assembly techniques) of C. elegans and H. sapiens transcript targets in their corresponding genomic space using whole genome shotgun sequencing reads. We also show that Kollector outperforms both established and recently released targeted assembly tools. Finally, we demonstrate three use cases for Kollector, including comparative and cancer genomics applications. Availability: Kollector is implemented as a bash script, and is available at https://github.com/bcgsc/kollector. Contact:ibirol@bcgsc.ca
Located in Platforms / Scientific Publications
Publication RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease.
by Stephanie McInnis published Feb 21, 2017
Background. Chronic fatigue syndrome (CFS) remains poorly understood. Although infections are speculated to trigger the syndrome, a specific infectious agent and underlying pathophysiological mechanism remain elusive. In a previous study, we described similar clinical phenotypes in CFS patients and alternatively diagnosed chronic Lyme syndrome (ADCLS) patients—individuals diagnosed with Lyme disease by testing from private Lyme specialty laboratories but who test negative by reference 2-tiered serologic analysis. Methods. Here, we performed blinded RNA-seq analysis of whole blood collected from 25 adults diagnosed with CFS and 13 ADCLS patients, comparing these cases to 25 matched controls and 11 patients with well-controlled systemic lupus erythematosus (SLE). Samples were collected at patient enrollment and not during acute symptom flares. RNA-seq data were used to study host gene expression, B-cell/T-cell receptor profiles (BCR/TCR), and potential viral infections. Results. No differentially expressed genes (DEGs) were found to be significant when CFS or ADCLS cases were compared to controls. Forty-two DEGs were found when SLE cases were compared to controls, consistent with activation of interferon signaling pathways associated with SLE disease. BCR/TCR repertoire analysis did not show significant differences between CFS and controls or ADCLS and controls. Finally, viral sequences corresponding to anelloviruses, human pegivirus 1, herpesviruses, and papillomaviruses were detected in RNA-seq data, but proportions were similar (P = .73) across all genus-level taxonomic categories. Conclusions. Our observations do not support a theory of transcriptionally mediated immune cell dysregulation in CFS and ADCLS, at least outside of periods of acute symptom flares.
Located in Platforms / Scientific Publications
Scientific Publications from the Personalized Oncogenomics study
by Stephanie McInnis published Feb 21, 2017 last modified Oct 09, 2017 09:26 PM
Located in Projects / Personalized Oncogenomics