CancerMine: a literature-mined resource for drivers, oncogenes and tumor suppressors in cancer.

Tumors from individuals with cancer are frequently genetically profiled for information about the driving forces behind the disease. We present the CancerMine resource, a text-mined and routinely updated database of drivers, oncogenes and tumor suppressors in different types of cancer. All data are available online ( http://bionlp.bcgsc.ca/cancermine ) and downloadable under a Creative Commons Zero license for ease of use.

Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series.

BACKGROUND: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors. PATIENTS AND METHODS: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib. RESULTS: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day. CONCLUSION: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors. KEY POINTS: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

Inhibition of Extracellular Enzymes Exposed to Cyanopeptides.

Harmful cyanobacterial blooms in freshwater ecosystems produce bioactive secondary metabolites including cyanopeptides that pose ecological and human health risks. Only adverse effects of one class of cyanopeptides, microcystins, have been studied extensively and have consequently been included in water quality assessments. Inhibition is a commonly observed effect for enzymes exposed to cyanopeptides and has mostly been investigated for human biologically relevant model enzymes. Here, we investigated the inhibition of ubiquitous aquatic enzymes by cyanobacterial metabolites. Hydrolytic enzymes are utilized in the metabolism of aquatic organisms and extracellularly by heterotrophic bacteria to obtain assimilable substrates. The ubiquitous occurrence of hydrolytic enzymes leads to the co-occurrence with cyanopeptides especially during cyanobacterial blooms. Bacterial leucine aminopeptidase and alkaline phosphatase were exposed to cyanopeptide extracts of different cyanobacterial strains ( Microcystis aeruginosa wild type and microcystin-free mutant, Planktothrix rubescens) and purified cyanopeptides. We observed inhibition of aminopeptidase and phosphatase upon exposure, especially to the apolar fractions of the cyanobacterial extracts. Exposure to the dominant cyanopeptides in these extracts confirmed that purified microcystins, aerucyclamide A and cyanopeptolin A inhibit the aminopeptidase in the low mg L-1 range while the phosphatase was less affected. Inhibition of aquatic enzymes can reduce the turnover of nutrients and carbon substrates and may also impair metabolic functions of grazing organisms.

A collaborative filtering-based approach to biomedical knowledge discovery.

Motivation: The increase in publication rates makes it challenging for an individual researcher to stay abreast of all relevant research in order to find novel research hypotheses. Literature-based discovery methods make use of knowledge graphs built using text mining and can infer future associations between biomedical concepts that will likely occur in new publications. These predictions are a valuable resource for researchers to explore a research topic. Current methods for prediction are based on the local structure of the knowledge graph. A method that uses global knowledge from across the knowledge graph needs to be developed in order to make knowledge discovery a frequently used tool by researchers. Results: We propose an approach based on the singular value decomposition (SVD) that is able to combine data from across the knowledge graph through a reduced representation. Using cooccurrence data extracted from published literature, we show that SVD performs better than the leading methods for scoring discoveries. We also show the diminishing predictive power of knowledge discovery as we compare our predictions with real associations that appear further into the future. Finally, we examine the strengths and weaknesses of the SVD approach against another well-performing system using several predicted associations. Availability and implementation: All code and results files for this analysis can be accessed at https://github.com/jakelever/knowledgediscovery. Contact: sjones@bcgsc.ca. Supplementary information: Supplementary data are available at Bioinformatics online.

msPurity: Automated Evaluation of Precursor Ion Purity for Mass Spectrometry-Based Fragmentation in Metabolomics.

Tandem mass spectrometry (MS/MS or MS2) is a widely used approach for structural annotation and identification of metabolites in complex biological samples. The importance of assessing the contribution of the precursor ion within an isolation window for MS2 experiments has been previously detailed in proteomics, where precursor ion purity influences the quality and accuracy of matching to mass spectral libraries, but to date, there has been little attention to this data-processing technique in metabolomics. Here, we present msPurity, a vendor-independent R package for liquid chromatography (LC) and direct infusion (DI) MS2 that calculates a simple metric to describe the contribution of the selected precursor. The precursor purity metric is calculated as "intensity of a selected precursor divided by the summed intensity of the isolation window". The metric is interpolated at the recorded point of MS2 acquisition using bordering full-scan spectra. Isotopic peaks of the selected precursor can be removed, and low abundance peaks that are believed to have limited contribution to the resulting MS2 spectra are removed. Additionally, the isolation efficiency of the mass spectrometer can be taken into account. The package was applied to Data Dependent Acquisition (DDA)-based MS2 metabolomics data sets derived from three metabolomics data repositories. For the 10 LC-MS2 DDA data sets with > ±1 Da isolation windows, the median precursor purity score ranged from 0.67 to 0.96 (scale = 0 to +1). The R package was also used to assess precursor purity of theoretical isolation windows from LC-MS data sets of differing sample types. The theoretical isolation windows being the same width used for an anticipated DDA experiment (±0.5 Da). The most complex sample had a median precursor purity score of 0.46 for the 64,498 XCMS determined features, in comparison to the less spectrally complex sample that had a purity score of 0.66 for 5071 XCMS features. It has been previously reported in proteomics that a purity score of <0.5 can produce unreliable spectra matching results. With this assumption, we show that for complex samples there will be a large number of metabolites where traditional DDA approaches will struggle to provide reliable annotations or accurate matches to mass spectral libraries.

RNA-seq analysis of the C. briggsae transcriptome.

Curation of a high-quality gene set is the critical first step in genome research, enabling subsequent analyses such as ortholog assignment, cis-regulatory element finding, and synteny detection. In this project, we have reannotated the genome of Caenorhabditis briggsae, the best studied sister species of the model organism Caenorhabditis elegans. First, we applied a homology-based gene predictor genBlastG to annotate the C. briggsae genome. We then validated and further improved the C. briggsae gene annotation through RNA-seq analysis of the C. briggsae transcriptome, which resulted in the first validated C. briggsae gene set (23,159 genes), among which 7347 genes (33.9% of all genes with introns) have all of their introns confirmed. Most genes (14,812, or 68.3%) have at least one intron validated, compared with only 3.9% in the most recent WormBase release (WS228). Of all introns in the revised gene set (103,083), 61,503 (60.1%) have been confirmed. Additionally, we have identified numerous trans-splicing leaders (SL1 and SL2 variants) in C. briggsae, leading to the first genome-wide annotation of operons in C. briggsae (1105 operons). The majority of the annotated operons (564, or 51.0%) are perfectly conserved in C. elegans, with an additional 345 operons (or 31.2%) somewhat divergent. Additionally, RNA-seq analysis revealed over 10 thousand small-size assembly errors in the current C. briggsae reference genome that can be readily corrected. The revised C. briggsae genome annotation represents a solid platform for comparative genomics analysis and evolutionary studies of Caenorhabditis species.

The ortholog of the human proto-oncogene ROS1 is required for epithelial development in C. elegans.

The orphan receptor ROS1 is a human proto-oncogene, mutations of which are found in an increasing number of cancers. Little is known about the role of ROS1, however in vertebrates it has been implicated in promoting differentiation programs in specialized epithelial tissues. In this study we show that the C. elegans ortholog of ROS1, the receptor tyrosine kinase ROL-3, has an essential role in orchestrating the morphogenesis and development of specialized epidermal tissues, highlighting a potentially conserved function in coordinating crosstalk between developing epithelial cells. We also provide evidence of a direct relationship between ROL-3, the mucin SRAP-1, and BCC-1, the homolog of mRNA regulating protein Bicaudal-C. This study answers a longstanding question as to the developmental function of ROL-3, identifies three new genes that are expressed and function in the developing epithelium of C. elegans, and introduces the nematode as a potentially powerful model system for investigating the increasingly important, yet poorly understood, human oncogene ROS1.

Lethal and sublethal effects towards zebrafish larvae of microcystins and other cyanopeptides produced by cyanobacteria.

Cyanobacterial blooms affect aquatic ecosystems across the globe and one major concern relates to their toxins such as microcystins (MC). Yet, the ecotoxicological risks, particularly non-lethal effects, associated with other co-produced secondary metabolites remain mostly unknown. Here, we assessed survival, morphological alterations, swimming behaviour and cardiovascular functions of zebrafish (Danio rerio) upon exposure to cyanobacterial extracts of two Brazilian Microcystis strains. We verified that only MIRS-04 produced MCs and identified other co-produced cyanopeptides also for the MC non-producer NPCD-01 by LC-HRMS/MS analysis. Both cyanobacterial extracts, from the MC-producer and non-producer, caused acute toxicity in zebrafish with LC50 values of 0.49 and 0.98 mgdw_biomass/mL, respectively. After exposure to MC-producer extract, additional decreased locomotor activity was observed. The cyanopeptolin (micropeptin K139) contributed 52% of the overall mortality and caused oedemas of the pericardial region. Oedemas of the pericardial area and prevented hatching were also observed upon exposure to the fraction with high abundance of a microginin (Nostoginin BN741) in the extract of the MC non-producer. Our results further add to the yet sparse understanding of lethal and sublethal effects caused by cyanobacterial metabolites other than MCs and the need to better understand the underlying mechanisms of the toxicity. We emphasize the importance of considering mixture toxicity of co-produced metabolites in the ecotoxicological risk assessment of cyanobacterial bloom events, given the importance for predicting adverse outcomes in fish and other organisms.

The atm-1 gene is required for genome stability in Caenorhabditis elegans.

The Ataxia-telangiectasia-mutated (ATM) gene in humans was identified as the basis of a rare autosomal disorder leading to cancer susceptibility and is now well known as an important signal transducer in response to DNA damage. An approach to understanding the conserved functions of this gene is provided by the model system, Caenorhabditis elegans. In this paper we describe the structure and loss of function phenotype of the ortholog atm-1. Using bioinformatic and molecular analysis we show that the atm-1 gene was previously misannotated. We find that the transcript is in fact a product of three gene predictions, Y48G1BL.2 (atm-1), K10E9.1, and F56C11.4 that together make up the complete coding region of ATM-1. We also characterize animals that are mutant for two available knockout alleles, gk186 and tm5027. As expected, atm-1 mutant animals are sensitive to ionizing radiation. In addition, however, atm-1 mutants also display phenotypes associated with genomic instability, including low brood size, reduced viability and sterility. We document several chromosomal fusions arising from atm-1 mutant animals. This is the first time a mutator phenotype has been described for atm-1 in C. elegans. Finally we demonstrate the use of a balancer system to screen for and capture atm-1-derived mutational events. Our study establishes C. elegans as a model for the study of ATM as a mutator potentially leading to the development of screens to identify therapeutic targets in humans.

The impact of whole genome and transcriptome analysis (WGTA) on predictive biomarker discovery and diagnostic accuracy of advanced malignancies.

In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non-MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non-contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.

A platform for oncogenomic reporting and interpretation.

Manual interpretation of variants remains rate limiting in precision oncology. The increasing scale and complexity of molecular data generated from comprehensive sequencing of cancer samples requires advanced interpretative platforms as precision oncology expands beyond individual patients to entire populations. To address this unmet need, we introduce a Platform for Oncogenomic Reporting and Interpretation (PORI), comprising an analytic framework that facilitates the interpretation and reporting of somatic variants in cancer. PORI integrates reporting and graph knowledge base tools combined with support for manual curation at the reporting stage. PORI represents an open-source platform alternative to commercial reporting solutions suitable for comprehensive genomic data sets in precision oncology. We demonstrate the utility of PORI by matching 9,961 pan-cancer genome atlas tumours to the graph knowledge base, calculating therapeutically informative alterations, and making available reports describing select individual samples.

CyanoMetDB, a comprehensive public database of secondary metabolites from cyanobacteria.

Harmful cyanobacterial blooms, which frequently contain toxic secondary metabolites, are reported in aquatic environments around the world. More than two thousand cyanobacterial secondary metabolites have been reported from diverse sources over the past fifty years. A comprehensive, publically-accessible database detailing these secondary metabolites would facilitate research into their occurrence, functions and toxicological risks. To address this need we created CyanoMetDB, a highly curated, flat-file, openly-accessible database of cyanobacterial secondary metabolites collated from 850 peer-reviewed articles published between 1967 and 2020. CyanoMetDB contains 2010 cyanobacterial metabolites and 99 structurally related compounds. This has nearly doubled the number of entries with complete literature metadata and structural composition information compared to previously available open access databases. The dataset includes microcytsins, cyanopeptolins, other depsipeptides, anabaenopeptins, microginins, aeruginosins, cyclamides, cryptophycins, saxitoxins, spumigins, microviridins, and anatoxins among other metabolite classes. A comprehensive database dedicated to cyanobacterial secondary metabolites facilitates: (1) the detection and dereplication of known cyanobacterial toxins and secondary metabolites; (2) the identification of novel natural products from cyanobacteria; (3) research on biosynthesis of cyanobacterial secondary metabolites, including substructure searches; and (4) the investigation of their abundance, persistence, and toxicity in natural environments.

Genomic sequence of a mutant strain of Caenorhabditis elegans with an altered recombination pattern.

BACKGROUND: The original sequencing and annotation of the Caenorhabditis elegans genome along with recent advances in sequencing technology provide an exceptional opportunity for the genomic analysis of wild-type and mutant strains. Using the Illumina Genome Analyzer, we sequenced the entire genome of Rec-1, a strain that alters the distribution of meiotic crossovers without changing the overall frequency. Rec-1 was derived from ethylmethane sulfonate (EMS)-treated strains, one of which had a high level of transposable element mobility. Sequencing of this strain provides an opportunity to examine the consequences on the genome of altering the distribution of meiotic recombination events. RESULTS: Using Illumina sequencing and MAQ software, 83% of the base pair sequence reads were aligned to the reference genome available at Wormbase, providing a 21-fold coverage of the genome. Using the software programs MAQ and Slider, we observed 1124 base pair differences between Rec-1 and the reference genome in Wormbase (WS190), and 441 between the mutagenized Rec-1 (BC313) and the wild-type N2 strain (VC2010). The most frequent base-substitution was G:C to A:T, 141 for the entire genome most of which were on chromosomes I or X, 55 and 31 respectively. With this data removed, no obvious pattern in the distribution of the base differences along the chromosomes was apparent. No major chromosomal rearrangements were observed, but additional insertions of transposable elements were detected. There are 11 extra copies of Tc1, and 8 of Tc2 in the Rec-1 genome, most likely the remains of past high-hopper activity in a progenitor strain. CONCLUSION: Our analysis of high-throughput sequencing was able to detect regions of direct repeat sequences, deletions, insertions of transposable elements, and base pair differences. A subset of sequence alterations affecting coding regions were confirmed by an independent approach using oligo array comparative genome hybridization. The major phenotype of the Rec-1 strain is an alteration in the preferred position of the meiotic recombination event with no other significant phenotypic consequences. In this study, we observed no evidence of a mutator effect at the nucleotide level attributable to the Rec-1 mutation.

Characterisation of the dynamic nature of lipids throughout the lifespan of genetically identical female and male Daphnia magna.

Lipids play a significant role in regulation of health and disease. To enhance our understanding of the role of lipids in regulation of lifespan and healthspan additional studies are required. Here, UHPLC-MS/MS lipidomics was used to measure dynamic changes in lipid composition as a function of age and gender in genetically identical male and female Daphnia magna with different average lifespans. We demonstrate statistically significant age-related changes in triglycerides (TG), diglycerides (DG), phosphatidylcholine, phosphatidylethanolamine, ceramide and sphingomyelin lipid groups, for example, in males, 17.04% of TG lipid species decline with age whilst 37.86% increase in relative intensity with age. In females, 23.16% decrease and 25.31% increase in relative intensity with age. Most interestingly, the rate and direction of change can differ between genetically identical female and male Daphnia magna, which could be the cause and/or the consequence of the different average lifespans between the two genetically identical genders. This study provides a benchmark dataset to understand how lipids alter as a function of age in genetically identical female and male species with different average lifespan and ageing rate.

Fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic DPYD structural variant.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors, the majority of which are treated with a combination of surgery, radiation, and chemotherapy. Fluoropyrimidine (5-FU) and its oral prodrug, capecitabine, are commonly prescribed treatments for several solid tumor types including HNSCC. 5-FU-associated toxicity is observed in ∼30% of treated patients and is largely caused by germline polymorphisms in DPYD, which encodes dihydropyrimidine dehydrogenase, a key enzyme of 5-FU catabolism and deactivation. Although the association of germline DPYD alterations with toxicity is well-described, the potential contribution of somatic DPYD alterations to 5-FU sensitivity has not been explored. In a patient with metastatic HNSCC, in-depth genomic and transcriptomic integrative analysis on a biopsy from a metastatic neck lesion revealed alterations in genes that are associated with 5-FU uptake and metabolism. These included a novel somatic structural variant resulting in a partial deletion affecting DPYD, a variant of unknown significance affecting SLC29A1, and homozygous deletion of MTAP There was no evidence of deleterious germline polymorphisms that have been associated with 5-FU toxicity, indicating a potential vulnerability of the tumor to 5-FU therapy. The discovery of the novel DPYD variant led to the initiation of 5-FU treatment that resulted in a rapid response lasting 17 wk, with subsequent relapse due to unknown resistance mechanisms. This suggests that somatic alterations present in this tumor may serve as markers for tumor sensitivity to 5-FU, aiding in the selection of personalized treatment strategies.

Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes.

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.

High-resolution array comparative genomic hybridization analysis reveals unanticipated complexity of genetic deficiencies on chromosome V in Caenorhabditis elegans.

Genomic rearrangements are widely used in Caenorhabditis elegans research but many remain incompletely characterized at the physical level. We have used oligo-array comparative genomic analysis to assess the physical structure of 20 deficiencies and a single duplication of chromosome V. We find that while deletions internal to the chromosome appear simple in structure, terminal deletions are complex, containing duplications in addition to the deletion. Additionally, we confirm that transposon-induced deficiencies contain breakpoints that initiate at Tc1 elements. Finally, 13 of these deficiencies are known to suppress recombination far beyond the extent of the deletion. These deficiencies fall into two classes: strong and weak suppressors of adjacent recombination. Analysis of the deleted regions in these deficiencies reveals no common physical sites to explain the observed differences in recombination suppression. However, we find a strong correlation between the size of the rearranged chromosome and the severity of recombination suppression. Rearranged chromosomes that have a minor effect on recombination fall within 2% of normal chromosome size. Our observations highlight the use of array-based approaches for the analysis of rearranged genomes, revealing previously unidentified deficiency characteristics and addressing biologically relevant questions.

Text-mining clinically relevant cancer biomarkers for curation into the CIViC database.

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/.

Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis.

We report a case of early-onset pancreatic ductal adenocarcinoma in a patient harboring biallelic MUTYH germline mutations, whose tumor featured somatic mutational signatures consistent with defective MUTYH-mediated base excision repair and the associated driver KRAS transversion mutation p.Gly12Cys. Analysis of an additional 730 advanced cancer cases (N = 731) was undertaken to determine whether the mutational signatures were also present in tumors from germline MUTYH heterozygote carriers or if instead the signatures were only seen in those with biallelic loss of function. We identified two patients with breast cancer each carrying a pathogenic germline MUTYH variant with a somatic MUTYH copy loss leading to the germline variant being homozygous in the tumor and demonstrating the same somatic signatures. Our results suggest that monoallelic inactivation of MUTYH is not sufficient for C:G>A:T transversion signatures previously linked to MUTYH deficiency to arise (N = 9), but that biallelic complete loss of MUTYH function can cause such signatures to arise even in tumors not classically seen in MUTYH-associated polyposis (N = 3). Although defective MUTYH is not the only determinant of these signatures, MUTYH germline variants may be present in a subset of patients with tumors demonstrating elevated somatic signatures possibly suggestive of MUTYH deficiency (e.g., COSMIC Signature 18, SigProfiler SBS18/SBS36, SignatureAnalyzer SBS18/SBS36).

NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma.

PURPOSE: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion-positive pancreatic ductal adenocarcinoma is not fully understood. EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. CONCLUSIONS: This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib.See related commentary by Aguirre, p. 4589.