Molecular Cancer Therapeutics, 2020
Authors
James T. Topham, Emma Titmuss, Erin D Pleasance, Laura M Williamson, Joanna M Karasinska, Luka Culibrk, Michael Kuan-Ching Lee, Shehara Mendis, Robert E Denroche, Gun-Ho Jang, Steve E Kalloger, Hui-Li Wong, Richard A Moore, Andrew J. Mungall, Grainne M O'Kane, Jennifer J. Knox, Steven Gallinger, Jonathan M Loree, Dixie L Mager, Janessa Laskin, Marco A. Marra, Steven JM Jones, David F Schaeffer and Daniel J Renouf
Publication Abstract

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. While expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic and clinical data across an integrated cohort of 199 metastatic breast, colorectal and pancreatic ductal adenocarcinoma (PDAC) patient tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2. Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation and immunogenicity.

British Journal of Haematology, 2020
Authors
Lourdes Calvente, Rosemarie Tremblay-LeMay, Wei Xu, Fong Chun Chan, Michael Hong, Tong Zhang, Ho-Young Yhim, John Kuruvilla, Michael Crump, Vishal Kukreti, Anca Prica, Dean Regier, Marco A Marra, Aly Karsan, Christian Steidl, David W Scott, Peter Sabatini, Robert Kridel.
Publication Abstract

Despite continuing improvements in the management of classical Hodgkin lymphoma (cHL), relapse remains associated with a risk of lymphoma-related mortality. The biological composition of relapse tumour biopsies shows interpatient variability, which can be leveraged to design prognostic biomarkers. Here, we validated the RHL30 assay, a previously reported gene expression model in an independent cohort of 41 patients with relapsed cHL. Patients classified as high-risk by the RHL30 assay had inferior failure-free survival (FFS) after autologous stem cell transplantation (2-year FFS 41% vs. 92%, P = 0·035). The RHL30 model is a robust biomarker that risk-stratifies patients considered for autologous stem cell transplantation.

Gigascience, 2020
Authors
Saber Hafezqorani, Chen Yang, Theodora Lo, Ka Ming Nip, René L Warren, Inanc Birol
Publication Abstract

Background: Compared with second-generation sequencing technologies, third-generation single-molecule RNA sequencing has unprecedented advantages; the long reads it generates facilitate isoform-level transcript characterization. In particular, the Oxford Nanopore Technology sequencing platforms have become more popular in recent years owing to their relatively high affordability and portability compared with other third-generation sequencing technologies. To aid the development of analytical tools that leverage the power of this technology, simulated data provide a cost-effective solution with ground truth. However, a nanopore sequence simulator targeting transcriptomic data is not available yet.

Findings: We introduce Trans-NanoSim, a tool that simulates reads with technical and transcriptome-specific features learnt from nanopore RNA-sequncing data. We comprehensively benchmarked Trans-NanoSim on direct RNA and complementary DNA datasets describing human and mouse transcriptomes. Through comparison against other nanopore read simulators, we show the unique advantage and robustness of Trans-NanoSim in capturing the characteristics of nanopore complementary DNA and direct RNA reads.

Conclusions: As a cost-effective alternative to sequencing real transcriptomes, Trans-NanoSim will facilitate the rapid development of analytical tools for nanopore RNA-sequencing data. Trans-NanoSim and its pre-trained models are freely accessible at https://github.com/bcgsc/NanoSim.

Nature Neuroscience, 2020
Authors
Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Lianne Q. Chau, Meher Beigi Masihi, Jessica M. Rusert, Paula S. Norris, Florent Carrette, Megan M. Romero, Sorana A. Morrissy, Patryk Skowron, Florence M. G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Steven J. M. Jones, Richard A. Moore, Andrew J. Mungall, Yussanne Ma, Nina Thiessen, Yisu Li, Alaide Morcavallo, Lin Qi, Mari Kogiso, Yuchen Du, Patricia Baxter, Jacob J. Henderson, John R. Crawford, Michael L. Levy, James M. Olson, Yoon-Jae Cho, Aniruddha J. Deshpande, Xiao-Nan Li, Louis Chesler, Marco A. Marra, Harald Wajant, Oren J. Becher, Linda M. Bradley, Carl F. Ware, Michael D. Taylor & Robert J. Wechsler-Reya
Publication Abstract

Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.

Genome Biology and Evolution, 2020
Authors
Shaun D Jackman, Lauren Coombe, René L Warren, Heather Kirk, Eva Trinh, Tina MacLeod, Stephen Pleasance, Pawan Pandoh, Yongjun Zhao, Robin J Coope, Jean Bousquet, Joerg Bohlmann, Steven J M Jones, Inanc Birol
Publication Abstract

Plant mitochondrial genomes vary widely in size. Although many plant mitochondrial genomes have been sequenced and assembled, the vast majority are of angiosperms, and few are of gymnosperms. Most plant mitochondrial genomes are smaller than a megabase, with a few notable exceptions. We have sequenced and assembled the complete 5.5 Mbp mitochondrial genome of Sitka spruce (Picea sitchensis), to date, one of the largest mitochondrial genomes of a gymnosperm. We sequenced the whole genome using Oxford Nanopore MinION, and then identified contigs of mitochondrial origin assembled from these long reads based on sequence homology to the white spruce mitochondrial genome. The assembly graph shows a multipartite genome structure, composed of one smaller 168 kbp circular segment of DNA, and a larger 5.4 Mbp single component with a branching structure. The assembly graph gives insight into a putative complex physical genome structure, and its branching points may represent active sites of recombination.

Clinical Cancer Research, 2020
Authors
Jennifer X Ji, Dawn R Cochrane, Basile Tessier-Cloutier, Shary Yuting Chen, Germain Ho, Khyatiben V Pathak, Isabel N Alcazar, David Farnell, Samuel Leung, Angela Cheng, Christine Chow, Shane Colborne, Gian Luca Negri, Friedrich Kommoss, Anthony Karnezis, Gregg B Morin, Jessica N McAlpine, Blake Gilks, Bernard E Weissman, Jeffrey M Trent, Lynn Hoang, Patrick Pirrotte, Yemin Wang, David G Huntsman.
Publication Abstract

Purpose: Many rare ovarian cancer subtypes such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) have poor prognosis due to their aggressive nature and resistance to standard platinum and taxane based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes.

Experimental design: We compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype high grade serous ovarian cancer (HGSC) to identify potential therapeutic targets. Immunohistochemistry of tissue microarrays were used as validation of ASS1 deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in-vitro using cell lines and patient derived xenograft mouse models representing SCCOHT.

Results: Global proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared to HGSC. Low ASS1 levels were validated through IHC in large patient cohorts. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 12/31 cases, and expressed in less than 5% of the tumor cells in 9/31 cases. ASS1 deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in-vitro Furthermore, in two cell line mouse xenograft models and one patient derived mouse xenograft model of SCCOHT, once a week treatment of ADI-PEG20 (30mg/kg and 15mg/kg) inhibited tumor growth in-vivo Conclusions: Preclinical in-vitro and in-vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers including SCCOHT.

Electrophoresis, 2020
Authors
Lingyu Wang, Jianhui Cheng, Julie E McNutt, Gregg B Morin, David D Y Chen.
Publication Abstract

Dynamic pH barrage junction focusing in CE enables effective signal enhancement, quantitative capture efficiencies, and straightforward optimization. The method is a technical variant of dynamic pH junction focusing. CE separation with dynamic pH barrage junction focusing is compatible with both optical and mass spectrometric detection. We developed a CE-MS/MS method using hydrophilic polyethyleneimine-coated capillaries and validated it for the qualitative analysis of amino acids, peptides, and tryptic peptides of digested monoclonal antibodies. The S/N of extracted ion electropherograms of zwitterionic analytes were enhanced by approximately two orders of magnitude with a tradeoff of a shortened separation window. Online focusing improved the MS signal intensity of a diluted antibody digest, enabling more precursor ions to be analyzed with subsequent tandem mass spectrometric identification. It also broadened the concentration range of protein digest samples for which adequate sequence coverage data can be obtained. With only 0.9 ng of digested infliximab sample loaded into the capillary, 76% and 100% sequence coverage was realized for antibody heavy and light chains, respectively, after online focusing. Full coverage was achieved with 9 ng of injected digest.

Nature communications, 2020
Authors
Evgin, Laura, Huff, Amanda L, Wongthida, Phonphimon, Thompson, Jill, Kottke, Tim, Tonne, Jason, Schuelke, Matthew, Ayasoufi, Katayoun, Driscoll, Christopher B, Shim, Kevin G, Reynolds, Pierce, Monie, Dileep D, Johnson, Aaron J, Coffey, Matt, Young, Sarah L, Archer, Gary, Sampson, John, Pulido, Jose, Perez, Luis Sanchez, Vile, Richard
Publication Abstract
The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNβ infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNβ. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.

Blood, 2020
Authors
Ryan D Morin, David W Scott

Cancer Cell, 2020
Authors
Jian Carrot-Zhang, Nyasha Chambwe, Jeffrey S Damrauer, Theo A Knijnenburg, A Gordon Robertson, Christina Yau, Wanding Zhou, Ashton C Berger, Kuan-Lin Huang, Justin Y Newberg, R Jay Mashl, Alessandro Romanel, Rosalyn W Sayaman, Francesca Demichelis, Ina Felau, Garrett M Frampton, Seunghun Han, Katherine A Hoadley, Anab Kemal, Peter W Laird, Alexander J Lazar, Xiuning Le, Ninad Oak, Hui Shen, Christopher K Wong, Jean C Zenklusen, Elad Ziv, Andrew D Cherniack, Rameen Beroukhim
Publication Abstract

We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes. Biologically significant differences were usually tissue specific but not specific to cancer. However, admixture and pathway analyses suggested some of these differences are causally related to cancer. Specific findings included increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.

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