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Supplemental Table S1 lists clinical characteristics for the study cohort. Figure S1 depicts results of batch correction. Figures S2 and S3 show comparisons between ERV levels and tumor content. Figure S4 shows ERV levels across different biopsy sites.

Supplemental Table S3 lists gene sets significantly enriched among genes up-regulated in VMP samples.

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. Although 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 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma 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.

Supplemental Table S4 lists gene sets significantly enriched among genes down-regulated in VMP samples.

Supplemental Table S5 lists EGA accession numbers for each sample included in the study.

Supplemental Table S2 lists all genes differentially expressed in VMP samples.

Heatmap showing median gene expression levels (z-score) of genes involved in various pathways related to cellular metabolism. For each gene, within each of the four metabolic subgroups, expression values were assessed for significant deviation from zero using Wilcoxon signed rank test (mu = 0).

Supplemental Figures and Tables

Purpose:Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis.Experimental Design:We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG).Results:On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P = 0.018) and metastatic settings (log-rank test P = 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC-amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes.Conclusions:Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles.See related commentary by Mehla and Singh, p. 6

Background Accelerated development of the platelet (PLT) storage lesion upon pathogen inactivation (PI) is associated with the release of proteins from granules and platelet microvesicles (PMVs). Whether PI treatments alter the interaction between PLT factors and the vessel endothelium is of interest in understanding the risk profile of these technologies. Study design and methods In a pool-and-split study, one platelet concentrate (PC) was treated with riboflavin/UV (RF/UV) light, while the other one was kept as an untreated control. Releasates and PMV-depleted releasates were prepared by differential centrifugation steps on days 0, 1, 5, and 7 of storage. Cytokine/chemokine release following PI treatment was analyzed by an antibody array, and results were verified by the enzyme-linked immunosorbent assay. PMVs were enumerated by CD41 labeling and flow cytometry. Wound scratch assays were performed using cultured Ea.hy926 cells exposed to the differently prepared releasates. Effects of releasates on the phosphorylation levels of kinases ERK and p38 expressed by endothelial cells were analyzed by immunoblot. Results Cytokine/chemokine assays identified a 2-fold increase in epidermal growth factor released from PCs treated with RF/UV light compared with control. PMV count increased ~100-fold following PI treatment. Unmodified releasates and PMV-depleted releasates displayed different contributions to the kinetics of endothelial cell wound closure. This observation was associated with an increased ERK versus unaltered p38 activation in the endothelial cells. Conclusion This study identified an inhibitory impact of PMVs on endothelial cell migration/proliferation upon stimulation by released cytokines and PMVs from PLTs treated with RF/UV light for endothelial cell wound closure.

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. Although 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 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma 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.

Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Polζ, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic. Marra and colleagues describe POG570, a pan-cancer, whole-genome, transcriptome and clinical dataset stressing the molecular interactions in advanced and post-therapy cancer patients.

Purpose: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis. Experimental Design: We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG). Results: On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P = 0.018) and metastatic settings (log-rank test P = 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC-amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes. Conclusions: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles. See related commentary by Mehla and Singh, p. 6

Background Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic, prognostic, predisposing, and drug response markers is essential. Several knowledgebases have been created by different groups to collate evidence for these associations. These include the open-access Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase. These databases rely on time-consuming manual curation from skilled experts who read and interpret the relevant biomedical literature. Methods To aid in this curation and provide the greatest coverage for these databases, particularly CIViC, we propose the use of text mining approaches to extract these clinically relevant biomarkers from all available published literature. To this end, a group of cancer genomics experts annotated sentences that discussed biomarkers with their clinical associations and achieved good inter-annotator agreement. We then used a supervised learning approach to construct the CIViCmine knowledgebase. Results We extracted 121,589 relevant sentences from PubMed abstracts and PubMed Central Open Access full-text papers. CIViCmine contains over 87,412 biomarkers associated with 8035 genes, 337 drugs, and 572 cancer types, representing 25,818 abstracts and 39,795 full-text publications. Conclusions Through integration with CIVIC, we provide a prioritized list of curatable clinically relevant cancer biomarkers as well as a resource that is valuable to other knowledgebases and precision cancer analysts in general. All data is publically available and distributed with a Creative Commons Zero license. The CIViCmine knowledgebase is available at http://bionlp.bcgsc.ca/civicmine/.

The highly diverse insect family of true weevils, Curculionidae, includes many agricultural and forest pests. Pissodes strobi, commonly known as the spruce weevil or white pine weevil, is a major pest of spruce and pine forests in North America. Pissodes strobi larvae feed on the apical shoots of young trees, causing stunted growth and can destroy regenerating spruce or pine forests. Here, we describe the nuclear and mitochondrial Pissodes strobi genomes and their annotations, as well as the genome of an apparent Wolbachia endosymbiont. We report a substantial expansion of the weevil nuclear genome, relative to other Curculionidae species, possibly driven by an abundance of class II DNA transposons. The endosymbiont observed belongs to a group (supergroup A) of Wolbachia species that generally form parasitic relationships with their arthropod host.

Adrenocortical cancer (ACC) is a rare cancer of the adrenal gland. Several driver mutations have been identified in both primary and metastatic ACCs, but the therapeutic options are still limited. We performed whole-genome and transcriptome sequencing on seven patients with metastatic ACC. Integrative analysis of mutations, RNA expression changes, mutation signature, and homologous recombination deficiency (HRD) analysis was performed. Mutations affecting

Cancers routinely exhibit chromosomal instability, resulting in the accumulation of changes in the abundance of genomic material, known as copy number variants (CNVs). Unfortunately, the detection of these variants in cancer genomes is difficult. We developed Ploidetect, a software package that effectively identifies CNVs within whole-genome sequenced tumors. Ploidetect was more sensitive to CNVs in cancer related genes within advanced, pre-treated metastatic cancers than other tools, while also segmenting the most contiguously. Chromosomal instability, as measured by segment contiguity, was associated with several biological and clinical variables, including tumor mutation burden, tumor type, duration of therapy and immune microenvironment, highlighting the relevance of measuring CNV across the cancer genome. Investigation of gene mutations in samples revealed and the mutation status of several genes including ROCK2 and AC074391.1. Leveraging our heightened ability to detect CNVs, we identified 282 genes which were recurrently homozygously deleted in metastatic tumors. Further analysis of one recurrently deleted gene, MACROD2, identified a putative fragile tumor suppressor locus associated with response to chromosomal instability and chemotherapeutic agents. Our results outline the multifaceted impacts of CNVs in cancer by providing evidence of their involvement in tumorigenic behaviors and their utility as biomarkers for biological processes. We propose that increasingly accurate determination of CNVs is critical for their productive study in cancer, and our work demonstrates advances made possible by progress in this regard.

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.

Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Polζ, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic.

The Steller sea lion is the largest member of the Otariidae family and is found in the coastal waters of the northern Pacific Rim. Here, we present the Steller sea lion genome, determined through DNA sequencing approaches that utilized microfluidic partitioning library construction, as well as nanopore technologies. These methods constructed a highly contiguous assembly with a scaffold N50 length of over 14 megabases, a contig N50 length of over 242 kilobases and a total length of 2.404 gigabases. As a measure of completeness, 95.1% of 4104 highly conserved mammalian genes were found to be complete within the assembly. Further annotation identified 19,668 protein coding genes. The assembled genome sequence and underlying sequence data can be found at the National Center for Biotechnology Information (NCBI) under the BioProject accession number PRJNA475770.

Opportunistic fungal infections are an increasing threat for global health, and for immunocompromised patients in particular. These infections are characterized by interaction between fungal pathogen and host cells. The exact mechanisms and the attendant variability in host and fungal pathogen interaction remain to be fully elucidated. The field of systems biology aims to characterize a biological system, and utilize this knowledge to predict the system's response to stimuli such as fungal exposures. A multi-omics approach, for example, combining data from genomics, proteomics, metabolomics, would allow a more comprehensive and pan-optic “two systems” biology of both the host and the fungal pathogen. In this review and literature analysis, we present highly specialized and nascent methods for analysis of multiple -omes of biological systems, in addition to emerging single-molecule visualization techniques that may assist in determining biological relevance of multi-omics data. We provide an overview of computational methods for modeling of gene regulatory networks, including some that have been applied towards the study of an interacting host and pathogen. In sum, comprehensive characterizations of host–fungal pathogen systems are now possible, and utilization of these cutting-edge multi-omics strategies may yield advances in better understanding of both host biology and fungal pathogens at a systems scale.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics., The driver mutations for the two main molecular subgroups of diffuse large B-cell lymphoma (DLBCL) are poorly defined. Here, an integrative genomics analysis identifies 3′ UTR NFKBIZ mutations within the activated B-cell DLBCL subgroup and small FCGR2B amplifications in the germinal centre B-cell DLBCL subgroup.

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

Variability in the immunogenic landscape of metastatic cancer lesions has revealed insight into detection of potential immunotherapy-responsive patients, though underlying mechanisms driving such variation are not fully understood. Endogenous retrovirus (ERV)-containing transcripts have recently emerged as a potential source of tumor-associated antigen that are orthogonal to somatic mutation-derived neoantigens. To characterize the intersection between ERV levels and predicted immunogenicity in metastatic cancer, we comprehensively profiled the transcript abundance of 702,533 ERV loci in 199 metastatic tumors from breast, colorectal, and pancreatic cancer patients. In all three cancer types, overall ERV transcript load was associated with upregulation of genes involved in innate antiviral response pathways as well as genes involved in both adaptive and innate immune signaling. In colorectal and pancreatic tumors, samples with concomitant increases in ERV load and antiviral response gene expression, termed viral mimicry tumors, showed high expression of the DNA demethylation gene TET2, a gene previously described to promote transcription of ERV-containing transcripts. Collectively, these data are compatible with the notion that an increased level of ERV-containing transcripts may account for increased immunogenicity in a subset of metastatic tumors and support the relationship between DNA demethylation and ERV load in colorectal and pancreatic tumors. Citation Format: James T. Topham, Emma Titmuss, Erin Pleasance, Laura M. Williamson, Joanna M. Karasinska, Luka Culibrk, Michael K.C. Lee, Steve E. Kalloger, Shehara Mendis, Richard A. Moore, Andrew J. Mungall, Janessa Laskin, Jonathan M. Loree, Dixie L. Mager, Marco A. Marra, Steven J.M. Jones, David F. Schaeffer, Daniel J. Renouf. Endogenous retrovirus transcript levels are associated with immunogenic signatures in multiple metastatic cancer types [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B56.

Reprogramming of metabolic pathways allows cancer cells to survive and thrive in the tumor microenvironment. Glycolysis-inducing factors including oncogenic KRAS mutations, loss of function in TP53 and hypoxia are prevalent in PDAC. Cholesterol and its metabolites support tumor cell growth and the mevalonate pathway, which uses glycolysis products for de novo cholesterol synthesis, has been found to be upregulated in cancer. However, whether intertumoral heterogeneity in these metabolic networks influences outcome in pancreatic cancer has not been well established. We profiled the expression of glycolytic and cholesterogenic genes in 325 resected and metastatic pancreatic ductal adenocarcinoma (PDAC) tumors and identified four distinct subgroups: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable and metastatic disease settings. Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of these oncogenes. The mitochondrial uptake of pyruvate, the end product of glycolysis, facilitates the generation of acetyl-CoA for cholesterol synthesis. PDAC tumors with a glycolytic gene signature had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of reported prognostic PDAC subtype classifier genes. Our results indicate that PDAC tumors have unique metabolic profiles that influence disease outcome and provide functional correlate to previously identified subtypes. The findings also raise the possibility of a shift in balance between the glycolytic and cholesterogenic pathways as a factor in PDAC progression and a potential target for therapy. Citation Format: Joanna M. Karasinska, James T. Topham, Steve E. Kalloger, Gun Ho Jang, Robert E. Denroche, Luka Culibrk, Laura M. Williamson, Hui-li Wong, Michael K.C. Lee, Grainne M. O'Kane, Richard A. Moore, Andrew J. Mungall, Malcolm J. Moore, Cassia Warren, Andrew Metcalfe, Faiyaz Notta, Jennifer J. Knox, Steven Gallinger, Janessa Laskin, Marco A. Marra, Steven J.M. Jones, Daniel J. Renouf, David F. Schaeffer. Gene expression along the glycolysis-cholesterol synthesis axis and outcome in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A24.

Background: Advanced pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality. There has been a rising incidence of early-onset pancreatic cancer (EOPC; ≤55 years). Reported treatment and survival outcomes in EOPC remain limited and have only been reported in the pre-FOLFIRINOX era. We characterized the genomic and transcriptomic landscapes of EOPC, while also leveraging provincial health data to investigate survival outcomes in advanced EOPC in a separate dataset. Methods: We generated a comprehensive and integrative dataset utilizing RNA-seq data and matched clinical metadata for 402 PDAC patients across 5 distinct studies and 4 sequencing centers, encompassing both resectable (ICGC, TCGA) and advanced (Personalized OncoGenomics and COMPASS) disease. 345 (85.8%) and 371 (92.3%) of samples had SNV/indel and CNV data available, respectively. Patients were stratified into EOPC (n=96), average-onset pancreatic cancer (AOPC, ≥70 years; n=121), and intermediate (>55 and Results: CDKN2A SNV/indels were identified in 22% and 26% of intermediate and AOPC patients, and in only 7% of EOPC patients (p Conclusions: Using an extensive PDAC sequencing dataset, we highlight a novel association between CDKN2A SNV/indel frequency and EOPC. Transcriptome-based analysis identified significant associations between age of onset and expression of synaptic signal transduction pathways. Collectively, these data indicate potential age-specific differences in the mutational and developmental trajectories of PDAC and generate novel hypotheses for further study of EOPC. Citation Format: Erica S. Tsang, James T. Topham, Joanna M. Karasinska, Michael K.C. Lee, Shehara Mendis, Luka Culibrk, Robert Denroche, Gun Ho Jang, Steve E. Kalloger, Richard A. Moore, Andrew J. Mungall, Janessa Laskin, Grainne M. O'Kane, Jennifer J. Knox, Steven Gallinger, Steven J. Jones, Marco A. Marra, Jonathan M. Loree, David F. Schaeffer, Daniel J. Renouf. Early-onset pancreatic ductal adenocarcinomas are characterized by a distinct mutational landscape [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B57.

3535 Background: Endogenous retrovirus (ERV) elements represent genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated increases in ERV mRNA as a result of DNA hypomethylation, and ERV transcription has been associated with increased immunogenicity in metastatic renal cell carcinoma. We performed comprehensive bioinformatics analysis of ERV transcription in metastatic colorectal carcinoma (mCRC), to identify novel links between ERV transcription, epigenetic dysregulation and immunogenicity in metastatic colorectal carcinoma (mCRC). Methods: Tumour samples from 63 patients with mCRC were subjected to RNA sequencing as part of the Personalized OncoGenomics program (POG; NCT02155621) at BC Cancer. Patients were enrolled between 07/2012-07/2017. ERV transcription was quantified across 702,533 distinct loci. Tumors were classified ERV-hi if their total ERV expression (RPKM) was greater than the mean across all samples. High antiviral gene expression tumors (AVG-hi) were designated as having a mean expression of IFIH1, DDX58, TLR3, TANK, TBKBP1, TBK1, IRF3 and IRF7 that was greater than the mean across all samples. All pairwise comparisons of gene expression were subjected to multiple hypothesis correction. Results: Median age was 59 years, with 34 (54%) male and 1 tumor microsatellite unstable. ERV-hi tumors showed increased expression of DNA demethylators TET2 ( q=0.0045) and TET3 ( q