Cancer Spectrum, 2020
Authors
Katherine Dixon, Sean Young, Yaoqing Shen,My Linh Thibodeau, Alexandra Fok, Erin Pleasance, Eric Zhao, Martin Jones, Geraldine Aubert, Linlea Armstrong, Alice Virani, Dean Regier, Karen Gelmon, Dan Renouf, Stephen Chia, Ian Bosdet, S Rod Rassekh, Rebecca J Deyell, Stephen Yip Ana Fisic, Emma Titmuss, Shirin Abadi, Steven J M Jones, Sophie Sun, Aly Karsan, Marco Marra, Janessa Laskin, Howard Lim, Kasmintan A Schrader
Publication Abstract

Inherited genetic variation has important implications for cancer screening, early diagnosis, and disease prognosis. A role for germline variation has also been described in shaping the molecular landscape, immune response, microenvironment, and treatment response of individual tumors. However, there is a lack of consensus on the handling and analysis of germline information that extends beyond known or suspected cancer susceptibility in large-scale cancer genomics initiatives. As part of the Personalized OncoGenomics program in British Columbia, we performed whole-genome and transcriptome sequencing in paired tumor and normal tissues from advanced cancer patients to characterize the molecular tumor landscape and identify putative targets for therapy. Overall, our experience supports a multidisciplinary and integrative approach to germline data management. This includes a need for broader definitions and standardized recommendations regarding primary and secondary germline findings in precision oncology. Here, we propose a framework for identifying, evaluating, and returning germline variants of potential clinical significance that may have indications for health management beyond cancer risk reduction or prevention in patients and their families.

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Nature Genetics, 2020
Authors
Alessia Gagliardi, Vanessa L Porter, Zusheng Zong, Reanne Bowlby, Emma Titmuss, Constance Namirembe, Nicholas B Griner, Hilary Petrello, Jay Bowen, Simon K Chan, Luka Culibrk, Teresa M Darragh, Mark H Stoler, Thomas C Wright, Patee Gesuwan, Maureen A Dyer, Yussanne Ma, Karen L Mungall, Steven J M Jones, Carolyn Nakisige, Karen Novik, Jackson Orem, Martin Origa, Julie M Gastier-Foster, Robert Yarchoan, Corey Casper, Gordon B Mills, Janet S Rader, Akinyemi I Ojesina, Daniela S Gerhard, Andrew J Mungall, Marco A Marra
Publication Abstract

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.

Molecular therapy : the journal of the American Society of Gene Therapy, 2020
Authors
Huff, Amanda L, Evgin, Laura, Thompson, Jill, Kottke, Tim, Driscoll, Christopher B, Tonne, Jason, Wongthida, Phonphimon, Schuelke, Matthew, Shim, Kevin G, Mer, Georges, Ramirez-Alvarado, Marina, Vile, Richard
Publication Abstract
Enhancing the immunogenicity of tumor-associated antigens would represent a major advance for anti-tumor vaccination strategies. Here, we investigated structure-directed antigen destabilization as a strategy to improve the degradation, immunogenic epitope presentation, and T cell activation against a vesicular stomatitis virus (VSV)-encoded tumor antigen. We used the crystal structure of the model antigen ovalbumin to identify charge-disrupting amino acid mutations that were predicted to decrease the stability of the protein. One mutation, OVA-C12R, significantly reduced the half-life of the protein and was preferentially degraded in a 26-S proteasomal-dependent manner. The destabilized ovalbumin protein exhibited enhanced presentation of the major histocompatibility complex (MHC) class I immunogenic epitope, SIINFEKL, on the surface of B16F10 cells or murine bone marrow-derived dendritic cells (BMDCs) in vitro. Enhanced presentation correlated with better recognition by cognate CD8 OT-I T cells as measured by activation, proliferation, and effector cytokine production. Finally, VSV encoding the degradation-prone antigen was better able to prime an antigen ovalbumin-specific CD8 T cell response in vivo without altering the anti-viral CD8 T cell response. Our studies highlight that not only is the choice of antigen in cancer vaccines of importance, but that emphasis should be placed on modifying antigen quality to ensure optimal priming of anti-tumor responses.

Nature genetics, 2020
Authors
Gagliardi, Alessia, Porter, Vanessa L, Zong, Zusheng, Bowlby, Reanne, Titmuss, Emma, Namirembe, Constance, Griner, Nicholas B, Petrello, Hilary, Bowen, Jay, Chan, Simon K, Culibrk, Luka, Darragh, Teresa M, Stoler, Mark H, Wright, Thomas C, Gesuwan, Patee, Dyer, Maureen A, Ma, Yussanne, Mungall, Karen L, Jones, Steven J M, Nakisige, Carolyn, Novik, Karen, Orem, Jackson, Origa, Martin, Gastier-Foster, Julie M, Yarchoan, Robert, Casper, Corey, Mills, Gordon B, Rader, Janet S, Ojesina, Akinyemi I, Gerhard, Daniela S, Mungall, Andrew J, Marra, Marco A
Publication Abstract

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV{{sup}}+{{/sup}}) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV{{sup}}+{{/sup}}, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.

Scientific Reports, 2020
Authors
Miguel Alcaide, Matthew Cheung, Jack Hillman, S Rod Rassekh, Rebecca J Deyell, Gerald Batist, Aly Karsan, Alexander W Wyatt, Nathalie Johnson, David W Scott, Ryan D Morin
Publication Abstract

Cell-free DNA (cfDNA) has become a comprehensive biomarker in the fields of non-invasive cancer detection and monitoring, organ transplantation, prenatal genetic testing and pathogen detection. While cfDNA samples can be obtained using a broad variety of approaches, there is an urgent need to standardize analytical tools aimed at assessing its basic properties. Typical methods to determine the yield and fragment size distribution of cfDNA samples are usually either blind to genomic DNA contamination or the presence of enzymatic inhibitors, which can confound and undermine downstream analyses. Here, we present a novel droplet digital PCR assay to identify suboptimal samples and aberrant cfDNA size distributions, the latter typically associated with high levels of circulating tumour DNA (ctDNA). Our assay was designed to promiscuously cross-amplify members of the human olfactory receptor (OR) gene family and includes a customizable diploid locus for the determination of absolute cfDNA concentrations. We demonstrate here the utility of our assay to estimate the yield and quality of cfDNA extracts and deduce fragment size distributions that correlate well with those inferred by capillary electrophoresis and high throughput sequencing. The assay described herein is a powerful tool to establish quality controls and stratify cfDNA samples based on presumed ctDNA levels, then facilitating the implementation of robust, cost-effective and standardized analytical workflows into clinical practice.

Cancers, 2020
Authors
Carmen A Banuelos, Yusuke Ito, Jon K Obst, Nasrin R Mawji, Jun Wang, Yukiyoshi Hirayama, Jacky K Leung, Teresa Tam, Amy H Tien, Raymond J Andersen, Marianne D Sadar
Publication Abstract

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

Bioinformatics, 2020
Authors
Sarah E I Perez, Aria S Hahn, Martin Krzywinski, Steven J Hallam
Publication Abstract

Motivation: Networks are used to relate topological structure to system dynamics and function, particularly in ecology and systems biology. Network analysis is often guided or complemented by data-driven visualization. Hive plots, one of many network visualizations, distinguish themselves as providing a general, consistent, and coherent rule-based representation to motivate hypothesis development and testing.

Results: Here, we present HyPE, Hive Panel Explorer, a software application that creates a panel of interactive hive plots. HyPE enables network exploration based on user-driven layout rules and parameter combinations for simultaneous rendering of multiple network views. We demonstrate HyPE's features by exploring a microbial co-occurrence network constructed from forest soil microbiomes.

Availability: HyPE is available under the GNU license: https://github.com/hallamlab/HivePanelExplorer. A wiki, including a tutorial, is available at https://github.com/hallamlab/HivePanelExplorer/wiki.

Supplementary information: Supplementary data are available at Bioinformatics online.

Cancer Epidemiology, Biomarkers & Prevention 2020
Authors
Freda M Warner, Maryam Darvishian, Terry Boyle, Angela R Brooks-Wilson, Joseph M Connors, Agnes S Lai, Nhu D Le, Kevin Song, Heather Sutherland, Ryan R Woods, Parveen Bhatti, John J Spinelli.
Publication Abstract

Background: Tattoos may cause a variety of adverse reactions in the body, including immune reactions and infections. However, it is unknown whether tattoos may increase the risk of lymphatic cancers such as non-Hodgkin Lymphoma (NHL) and multiple myeloma (MM).

Methods: Participants from two population-based case-control studies were including in logistic regression models to examine the association between tattoos and risk of NHL and MM.

Results: A total of 1518 participants from the NHL study (737 cases) and 742 participants from the MM study (373 cases) were included in the analyses. No statistically significant associations were found between tattoos and risk of NHL or MM after adjusting for age, sex, ethnicity, education, BMI, and family history.

Conclusions: We did not identify any significant associations between tattoos and risk of MM, NHL, or NHL subtypes in these studies.

Impact: Though biologically plausible, tattoos were not associated with increased risk of NHL or MM in this study. Future studies with greater detail regarding tattoo exposure may provide further insights.

Epigenomics, 2020
Authors
Luolan Li, Cecile L Maire, Misha Bilenky, Annaïck Carles, Alireza Heravi-Moussavi, Chibo Hong, Angela Tam, Baljit Kamoh, Stephanie Cho, Dorothy Cheung, Irene Li, Tina Wong, Raman P Nagarajan, Andrew J Mungall, Richard Moore, Ting Wang, Claudia L Kleinman, Nada Jabado, Steven Jm Jones, Marco A Marra, Keith L Ligon, Joseph F Costello, Martin Hirst
Publication Abstract

Aim: To provide a comprehensive understanding of gene regulatory networks in the developing human brain and a foundation for interpreting pathogenic deregulation. Materials & methods: We generated reference epigenomes and transcriptomes of dissected brain regions and primary neural progenitor cells (NPCs) derived from cortical and ganglionic eminence tissues of four normal human fetuses. Results: Integration of these data across developmental stages revealed a directional increase in active regulatory states, transcription factor activities and gene transcription with developmental stage. Consistent with differences in their biology, NPCs derived from cortical and ganglionic eminence regions contained common, region specific, and gestational week specific regulatory states. Conclusion: We provide a high-resolution regulatory network for NPCs from different brain regions as a comprehensive reference for future studies.

Breast Cancer Research And Treatment, 2020
Authors
Svetlana Bortnik, Basile Tessier-Cloutier, Samuel Leung, Jing Xu, Karama Asleh, Samantha Burugu, Jamie Magrill, Kendall Greening, Fatemeh Derakhshan, Stephen Yip, Tony Ng, Karen A Gelmon, Torsten O Nielsen, Sharon M Gorski
Publication Abstract

Purpose: Previous studies indicate that breast cancer molecular subtypes differ with respect to their dependency on autophagy, but our knowledge of the differential expression and prognostic significance of autophagy-related biomarkers in breast cancer is limited.

Methods: Immunohistochemistry (IHC) was performed on tissue microarrays from a large population of 3992 breast cancer patients divided into training and validation cohorts. Consensus staining scores were used to evaluate the expression levels of autophagy proteins LC3B, ATG4B, and GABARAP and determine the associations with clinicopathological variables and molecular biomarkers. Survival analyses were performed using the Kaplan-Meier function and Cox proportional hazards regression models.

Results: We found subtype-specific expression differences for ATG4B, with its expression lowest in basal-like breast cancer and highest in Luminal A, but there were no significant associations with patient prognosis. LC3B and GABARAP levels were highest in basal-like breast cancers, and high levels were associated with worse outcomes across all subtypes (DSS; GABARAP: HR 1.43, LC3B puncta: HR 1.43). High ATG4B levels were associated with ER, PR, and BCL2 positivity, while high LC3B and GABARAP levels were associated with ER, PR, and BCL2 negativity, as well as EGFR, HER2, HER3, CA-IX, PD-L1 positivity, and high Ki67 index (p < 0.05 for all associations). Exploratory multi-marker analysis indicated that the combination of ATG4B and GABARAP with LC3B could be useful for further stratifying patient outcomes.

Conclusions: ATG4B levels varied across breast cancer subtypes but did not show prognostic significance. High LC3B expression and high GABARAP expression were both associated with poor prognosis and with clinicopathological characteristics of aggressive disease phenotypes in all breast cancer subtypes.

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