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Publication image/x-jg Innovations and challenges in detecting long read overlaps: an evaluation of the state-of-the-art.
by Stephanie McInnis published Feb 21, 2017
Identifying overlaps between error-prone long reads, specifically those from Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PB), is essential for certain downstream applications, including error correction and de novo assembly. Though akin to the read-to-reference alignment problem, read-to-read overlap detection is a distinct problem that can benefit from specialized algorithms that perform efficiently and robustly on high error rate long reads. Here, we review the current state-of-the-art read-to-read overlap tools for error-prone long reads, including BLASR, DALIGNER, MHAP, GraphMap, and Minimap. These specialized bioinformatics tools differ not just in their algorithmic designs and methodology, but also in their robustness of performance on a variety of datasets, time and memory efficiency, and scalability. We highlight the algorithmic features of these tools, as well as their potential issues and biases when utilizing any particular method. To supplement our review of the algorithms, we benchmarked these tools, tracking their resource needs and computational performance, and assessed the specificity and precision of each. In the versions of the tools tested, we observed that Minimap is the most computationally efficient, specific and sensitive method on the ONT datasets tested; whereas GraphMap and DALIGNER are the most specific and sensitive methods on the tested PB datasets. The concepts surveyed may apply to future sequencing technologies, as scalability is becoming more relevant with increased sequencing throughput.
Located in Platforms / Scientific Publications
Publication Mathematica Notebook Integrated genomic characterization of oesophageal carcinoma.
by Stephanie McInnis published Feb 21, 2017
Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.
Located in Platforms / Scientific Publications
Publication Personalized oncogenomics in the management of gastrointestinal carcinomas-early experiences from a pilot study.
by Stephanie McInnis published Feb 21, 2017 last modified Feb 21, 2017 06:02 PM
Background Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways. Methods We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma. Results In the first case, genomic profiling revealed an IDH1 somatic mutation, supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin, and further guided therapy by identifying epidermal growth factor receptor amplification. In the second case, a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma. The third case was an appendiceal adenocarcinoma defined by a p53 inactivation; Ras/raf/mek, Akt/mtor, Wnt, and notch pathway activation; and overexpression of ret, erbb2 (her2), erbb3, met, and cell cycle regulators. Summary We show that whole-genome and transcriptome sequencing can be achieved within clinically effective timelines, yielding clinically useful and actionable information. Keywords: Oncogenomics, genomics, cholangiocarcinoma, colonic adenocarcinoma, appendiceal adenocarcinoma, targeted therapy, personalized medicine, bevacizumab
Located in Platforms / Scientific Publications
Publication Octet Stream ntCard: A streaming algorithm for cardinality estimation in genomics data.
by Stephanie McInnis published Feb 21, 2017
Many bioinformatics algorithms are designed for the analysis of sequences of some uniform length, conventionally referred to as k-mers. These include de Bruijn graph assembly methods and sequence alignment tools. An efficient algorithm to enumerate the number of unique k-mers, or even better, to build a histogram of k-mer frequencies would be desirable for these tools and their downstream analysis pipelines. Among other applications, estimated frequencies can be used to predict genome sizes, measure sequencing error rates, and tune runtime parameters for analysis tools. However, calculating a k-mer histogram from large volumes of sequencing data is a challenging task.
Located in Platforms / Scientific Publications
Publication Octet Stream Characterization of treatment and outcomes in a population-based cohort of patients with chronic lymphocytic leukemia referred for cytogenetic testing in British Columbia, Canada.
by Stephanie McInnis published Feb 21, 2017
This study evaluates outcomes in chronic lymphocytic leukemia (CLL) based on first-line therapy in a large consecutive population-based cohort of 669 patients with fluorescence in-situ hybridization (FISH) data in British Columbia, Canada during the period when chemoimmunotherapy was standard first-line treatment. When analyzed as a time-dependent variable, patients who required treatment (n=336) had a 4.7 times higher hazard of death than patients who did not (95% confidence interval 2.8-7.9, P<0.001). The majority of patients received fludarabine-rituximab (FR) in front-line. On multivariate Cox regression analysis, fludarabine-based first-line therapy predicted longer time-to-next-treatment (TTNT) (HR 0.53, 95% confidence interval 0.33-0.87, P=0.012) but no difference in overall survival (OS) compared to alkylator-based therapy. Deletion 17p was an independent predictor of worse TTNT and OS. The most common second-line treatments were cyclophosphamide-vincristine-prednisone-rituximab and FR. There was no difference in OS between patients retreated in second-line with the same first-line regimen (n=33) versus different regimen (n=113). In conclusion, front-line treatment with fludarabine leads to a longer time until need for next treatment than alkylator-based therapy; however, fludarabine or alkylator therapy produces no difference in OS. This study provides a historical baseline for the comparison of novel agents with standard treatments in CLL on a population-level.
Located in Platforms / Scientific Publications
Publication chemical/x-cerius Integrated genomic and molecular characterization of cervical cancer.
by Stephanie McInnis published Feb 21, 2017
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, the largest comprehensive genomic study of cervical cancer to date. We observed striking APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered novel amplifications in immune targets CD274/PD-L1 and PDCD1LG2/PD-L2, and the BCAR4 lncRNA that has been associated with response to lapatinib. HPV integration was observed in all HPV18-related cases and 76% of HPV16-related cases, and was associated with structural aberrations and increased target gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumors with high frequencies of KRAS, ARID1A, and PTEN mutations. Integrative clustering of 178 samples identified Keratin-low Squamous, Keratin-high Squamous, and Adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.
Located in Platforms / Scientific Publications
Publication Cell-Based Therapeutics: Making a Faustian Pact with Biology.
by Stephanie McInnis published Feb 21, 2017
The diversity and specialization found in biological molecules, pathways, and cells is staggering, and should be exploited for therapeutic use. Through evolution these biological systems have attained a level of functionality that would be impossible to recapitulate with de novo assembly. To adapt these systems for therapeutic applications it will be often necessary to re-engineer molecules and pathways to yield novel sensory, control, and effector modules for insertion into existing, specialized cellular chassis. However, these efforts will be greatly impeded and confounded by the noise, complexity, and context-dependency inherent in biological systems. Thus, we argue that repurposing biology for cell-based therapeutics will be an arduous process, but one that will yield great benefit, and is superior to any alternative.
Located in Platforms / Scientific Publications
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