Publications

@article{brereton_reanalysis_2021,

title = {Reanalysis of the Mars500 experiment reveals common gut microbiome alterations in astronauts induced by long-duration confinement},

author = {N J B Brereton and F E Pitre and E Gonzalez},

url = {https://www.sciencedirect.com/science/article/pii/S2001037021001306},

doi = {10.1016/j.csbj.2021.03.040},

issn = {2001-0370},

year  = {2021},

date = {2021-01-01},

urldate = {2021-05-28},

journal = {Computational and Structural Biotechnology Journal},

volume = {19},

pages = {2223--2235},

abstract = {Maintaining astronaut health throughout long-duration spaceflight is essential to the feasibility of a manned mission to Mars. The ground-based Mars500 experiment investigated long-duration health by isolating six astronauts for 520 days, the longest controlled human confinement study conducted to date. After 520 days, astronauts had uniform strength and lean body mass losses, and increased fasting plasma glucose, calprotectin, and neutrophil levels characteristic of intestinal inflammation but previous analyses revealed no common significant changes in gut microbiota. This study reanalysed data from early (days 7–45) and late (days 420–520) faecal samples and identified 408 exact sequence variants (ESVs), including 213 shared by all astronauts. Thirty-two ESVs were significantly differentially abundant over time, including depletion of keystone resistant starch degrading, anti-inflammatory and insulin sensitivity-associated species, such as Faecalibacterium prausnitzii, Ruminococcus bromii, Blautia luti, Anaerostipes hadrus, Roseburia faecis, and Lactobacillus rogosae, and enrichment of yet-to-be-cultured bacteria. Additionally, the extraordinary experimental confinement allowed observation of microbiota potentially shared between astronauts and their habitat. Forty-nine species were shared, representing 49% and 12% of the human and environmental microbiome diversity, respectively. These findings reveal the microbiota which significantly altered in relative abundance throughout confinement, including species known to influence inflammation and host glucose homeostasis consistent with astronaut symptoms. Identification of microbiome alterations after 520 days of isolation represents a missing piece connecting Mars500 astronaut physiological studies. Knowledge of the impact of long-term confinement upon the human microbiome helps to improve our understanding of how humans interact with their habitats and is a valuable step forward towards enabling long-duration spaceflight.},

keywords = {16S rRNA gene, Astronaut health, Mars, Microbiome, Space science},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34590283b,

title = {Inferring Copy Number from Triple-Negative Breast Cancer Patient Derived Xenograft scRNAseq Data Using scCNA},

author = {Elena Kuzmin and Jean Monlong and Constanza Martinez and Hellen Kuasne and Claudia L Kleinman and Jiannis Ragoussis and Guillaume Bourque and Morag Park},

doi = {10.1007/978-1-0716-1740-3_16},

issn = {1940-6029},

year  = {2021},

date = {2021-01-01},

journal = {Methods Mol Biol},

volume = {2381},

pages = {285--303},

abstract = {Cancer can develop from an accumulation of alterations, some of which cause a nonmalignant cell to transform to a malignant state exhibiting increased rate of cell growth and evasion of growth suppressive mechanisms, eventually leading to tissue invasion and metastatic disease. Triple-negative breast cancers (TNBC) are heterogeneous and are clinically characterized by the lack of expression of hormone receptors and human epidermal growth factor receptor 2 (HER2), which limits its treatment options. Since tumor evolution is driven by diverse cancer cell populations and their microenvironment, it is imperative to map TNBC at single-cell resolution. Here, we describe an experimental procedure for isolating a single-cell suspension from a TNBC patient-derived xenograft, subjecting it to single-cell RNA sequencing using droplet-based technology from 10× Genomics and analyzing the transcriptomic data at single-cell resolution to obtain inferred copy number aberration profiles, using scCNA. Data obtained using this single-cell RNA sequencing experimental and analytical methodology should enhance our understanding of intratumor heterogeneity which is key for identifying genetic vulnerabilities and developing effective therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34335193b,

title = {Single Cell Transcriptomics of Ependymal Cells Across Age, Region and Species Reveals Cilia-Related and Metal Ion Regulatory Roles as Major Conserved Ependymal Cell Functions},

author = {Adam MacDonald and Brianna Lu and Maxime Caron and Nina Caporicci-Dinucci and Dale Hatrock and Kevin Petrecca and Guillaume Bourque and Jo Anne Stratton},

doi = {10.3389/fncel.2021.703951},

issn = {1662-5102},

year  = {2021},

date = {2021-01-01},

journal = {Front Cell Neurosci},

volume = {15},

pages = {703951},

abstract = {Ependymal cells are ciliated-epithelial glial cells that develop from radial glia along the surface of the ventricles of the brain and the spinal canal. They play a critical role in cerebrospinal fluid (CSF) homeostasis, brain metabolism, and the clearance of waste from the brain. These cells have been implicated in disease across the lifespan including developmental disorders, cancer, and neurodegenerative disease. Despite this, ependymal cells remain largely understudied. Using single-cell RNA sequencing data extracted from publicly available datasets, we make key findings regarding the remarkable conservation of ependymal cell gene signatures across age, region, and species. Through this unbiased analysis, we have discovered that one of the most overrepresented ependymal cell functions that we observed relates to a  understudied role in metal ion homeostasis. Our analysis also revealed distinct subtypes and states of ependymal cells across regions and ages of the nervous system. For example, neonatal ependymal cells maintained a gene signature consistent with developmental processes such as determination of left/right symmetry; while adult ventricular ependymal cells, not spinal canal ependymal cells, appeared to express genes involved in regulating cellular transport and inflammation. Together, these findings highlight underappreciated functions of ependymal cells, which will be important to investigate in order to better understand these cells in health and disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34194450b,

title = {The Cowpea Kinome: Genomic and Transcriptomic Analysis Under Biotic and Abiotic Stresses},

author = {José Ribamar Costa Ferreira-Neto and Artemisa Nazaré da Costa Borges and Manassés Daniel da Silva and David Anderson de Lima Morais and João Pacífico Bezerra-Neto and Guillaume Bourque and Ederson Akio Kido and Ana Maria Benko-Iseppon},

doi = {10.3389/fpls.2021.667013},

issn = {1664-462X},

year  = {2021},

date = {2021-01-01},

journal = {Front Plant Sci},

volume = {12},

pages = {667013},

abstract = {The present work represents a pioneering effort, being the first to analyze genomic and transcriptomic data from  (cowpea) kinases. We evaluated the cowpea kinome considering its genome-wide distribution and structural characteristics (at the gene and protein levels), sequence evolution, conservation among Viridiplantae species, and gene expression in three cowpea genotypes under different stress situations, including biotic (injury followed by virus inoculation-CABMV or CPSMV) and abiotic (root dehydration). The structural features of cowpea kinases (VuPKs) indicated that 1,293  VuPKs covered 20 groups and 118 different families. The RLK-Pelle was the largest group, with 908 members. Insights on the mechanisms of VuPK genomic expansion and conservation among Viridiplantae species indicated dispersed and tandem duplications as major forces for VuPKs' distribution pattern and high orthology indexes and synteny with other legume species, respectively.   /  ratios showed that almost all (91%) of the tandem duplication events were under purifying selection. Candidate -regulatory elements were associated with different transcription factors (TFs) in the promoter regions of the RLK-Pelle group. C2H2 TFs were closely associated with the promoter regions of almost all scrutinized families for the mentioned group. At the transcriptional level, it was suggested that VuPK up-regulation was stress, genotype, or tissue dependent (or a combination of them). The most prominent families in responding (up-regulation) to all the analyzed stresses were RLK-Pelle_DLSV and CAMK_CAMKL-CHK1. Concerning root dehydration, it was suggested that the up-regulated VuPKs are associated with ABA hormone signaling, auxin hormone transport, and potassium ion metabolism. Additionally, up-regulated VuPKs under root dehydration potentially assist in a critical physiological strategy of the studied cowpea genotype in this assay, with activation of defense mechanisms against biotic stress while responding to root dehydration. This study provides the foundation for further studies on the evolution and molecular function of VuPKs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33168820b,

title = {Paired rRNA-depleted and polyA-selected RNA sequencing data and supporting multi-omics data from human T cells},

author = {Li Chen and Ruirui Yang and Tony Kwan and Chao Tang and Stephen Watt and Yiming Zhang and Guillaume Bourque and Bing Ge and Kate Downes and Mattia Frontini and Willem H Ouwehand and Jing-Wen Lin and Nicole Soranzo and Tomi Pastinen and Lu Chen},

doi = {10.1038/s41597-020-00719-4},

issn = {2052-4463},

year  = {2020},

date = {2020-11-01},

journal = {Sci Data},

volume = {7},

number = {1},

pages = {376},

abstract = {Both poly(A) enrichment and ribosomal RNA depletion are commonly used for RNA sequencing. Either has its advantages and disadvantages that may lead to biases in the downstream analyses. To better access these effects, we carried out both ribosomal RNA-depleted and poly(A)-selected RNA-seq for CD4 T naive cells isolated from 40 healthy individuals from the Blueprint Project. For these 40 individuals, the genomic and epigenetic data were also available. This dataset offers a unique opportunity to understand how library construction influences differential gene expression, alternative splicing and molecular QTL (quantitative loci) analyses for human primary cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32958763b,

title = {Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples},

author = {Matthew H Bailey and William U Meyerson and Lewis Jonathan Dursi and Liang-Bo Wang and Guanlan Dong and Wen-Wei Liang and Amila Weerasinghe and Shantao Li and Yize Li and Sean Kelso and  and  and Gordon Saksena and Kyle Ellrott and Michael C Wendl and David A Wheeler and Gad Getz and Jared T Simpson and Mark B Gerstein and Li Ding and },

doi = {10.1038/s41467-020-18151-y},

issn = {2041-1723},

year  = {2020},

date = {2020-09-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {4748},

abstract = {The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32859912b,

title = {Sex differences in oncogenic mutational processes},

author = {Constance H Li and Stephenie D Prokopec and Ren X Sun and Fouad Yousif and Nathaniel Schmitz and  and Paul C Boutros and },

doi = {10.1038/s41467-020-17359-2},

issn = {2041-1723},

year  = {2020},

date = {2020-08-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {4330},

abstract = {Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32641768b,

title = {Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy},

author = {Charles P Couturier and Shamini Ayyadhury and Phuong U Le and Javad Nadaf and Jean Monlong and Gabriele Riva and Redouane Allache and Salma Baig and Xiaohua Yan and Mathieu Bourgey and Changseok Lee and Yu Chang David Wang and V Wee Yong and Marie-Christine Guiot and Hamed Najafabadi and Bratislav Misic and Jack Antel and Guillaume Bourque and Jiannis Ragoussis and Kevin Petrecca},

doi = {10.1038/s41467-020-17186-5},

issn = {2041-1723},

year  = {2020},

date = {2020-07-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {3406},

abstract = {Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32527045b,

title = {Sex Chromosomes and Sex Phenotype Contribute to Biased DNA Methylation in Mouse Liver},

author = {Qinwei Kim-Wee Zhuang and Jose Hector Galvez and Qian Xiao and Najla AlOgayil and Jeffrey Hyacinthe and Teruko Taketo and Guillaume Bourque and Anna K Naumova},

doi = {10.3390/cells9061436},

issn = {2073-4409},

year  = {2020},

date = {2020-06-01},

journal = {Cells},

volume = {9},

number = {6},

abstract = {Sex biases in the genome-wide distribution of DNA methylation and gene expression levels are some of the manifestations of sexual dimorphism in mammals. To advance our understanding of the mechanisms that contribute to sex biases in DNA methylation and gene expression, we conducted whole genome bisulfite sequencing (WGBS) as well as RNA-seq on liver samples from mice with different combinations of sex phenotype and sex-chromosome complement. We compared groups of animals with different sex phenotypes, but the same genetic sexes, and vice versa, same sex phenotypes, but different sex-chromosome complements. We also compared sex-biased DNA methylation in mouse and human livers. Our data show that sex phenotype, X-chromosome dosage, and the presence of Y chromosome shape the differences in DNA methylation between males and females. We also demonstrate that sex bias in autosomal methylation is associated with sex bias in gene expression, whereas X-chromosome dosage-dependent methylation differences are not, as expected for a dosage-compensation mechanism. Furthermore, we find partial conservation between the repertoires of mouse and human genes that are associated with sex-biased methylation, an indication that gene function is likely to be an important factor in this phenomenon.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32450900b,

title = {Personalized and graph genomes reveal missing signal in epigenomic data},

author = {Cristian Groza and Tony Kwan and Nicole Soranzo and Tomi Pastinen and Guillaume Bourque},

doi = {10.1186/s13059-020-02038-8},

issn = {1474-760X},

year  = {2020},

date = {2020-05-01},

journal = {Genome Biol},

volume = {21},

number = {1},

pages = {124},

abstract = {BACKGROUND: Epigenomic studies that use next generation sequencing experiments typically rely on the alignment of reads to a reference sequence. However, because of genetic diversity and the diploid nature of the human genome, we hypothesize that using a generic reference could lead to incorrectly mapped reads and bias downstream results.



RESULTS: We show that accounting for genetic variation using a modified reference genome or a de novo assembled genome can alter histone H3K4me1 and H3K27ac ChIP-seq peak calls either by creating new personal peaks or by the loss of reference peaks. Using permissive cutoffs, modified reference genomes are found to alter approximately 1% of peak calls while de novo assembled genomes alter up to 5% of peaks. We also show statistically significant differences in the amount of reads observed in regions associated with the new, altered, and unchanged peaks. We report that short insertions and deletions (indels), followed by single nucleotide variants (SNVs), have the highest probability of modifying peak calls. We show that using a graph personalized genome represents a reasonable compromise between modified reference genomes and de novo assembled genomes. We demonstrate that altered peaks have a genomic distribution typical of other peaks.



CONCLUSIONS: Analyzing epigenomic datasets with personalized and graph genomes allows the recovery of new peaks enriched for indels and SNVs. These altered peaks are more likely to differ between individuals and, as such, could be relevant in the study of various human phenotypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32415257b,

title = {Single-cell analysis of childhood leukemia reveals a link between developmental states and ribosomal protein expression as a source of intra-individual heterogeneity},

author = {Maxime Caron and Pascal St-Onge and Thomas Sontag and Yu Chang Wang and Chantal Richer and Ioannis Ragoussis and Daniel Sinnett and Guillaume Bourque},

doi = {10.1038/s41598-020-64929-x},

issn = {2045-2322},

year  = {2020},

date = {2020-05-01},

journal = {Sci Rep},

volume = {10},

number = {1},

pages = {8079},

abstract = {Childhood acute lymphoblastic leukemia (cALL) is the most common pediatric cancer. It is characterized by bone marrow lymphoid precursors that acquire genetic alterations, resulting in disrupted maturation and uncontrollable proliferation. More than a dozen molecular subtypes of variable severity can be used to classify cALL cases. Modern therapy protocols currently cure 85-90% of cases, but other patients are refractory or will relapse and eventually succumb to their disease. To better understand intratumor heterogeneity in cALL patients, we investigated the nature and extent of transcriptional heterogeneity at the cellular level by sequencing the transcriptomes of 39,375 individual cells in eight patients (six B-ALL and two T-ALL) and three healthy pediatric controls. We observed intra-individual transcriptional clusters in five out of the eight patients. Using pseudotime maturation trajectories of healthy B and T cells, we obtained the predicted developmental state of each leukemia cell and observed distribution shifts within patients. We showed that the predicted developmental states of these cancer cells are inversely correlated with ribosomal protein expression levels, which could be a common contributor to intra-individual heterogeneity in cALL patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32075553b,

title = {Transposable elements have contributed human regulatory regions that are activated upon bacterial infection},

author = {Lucia Bogdan and Luis Barreiro and Guillaume Bourque},

doi = {10.1098/rstb.2019.0332},

issn = {1471-2970},

year  = {2020},

date = {2020-03-01},

journal = {Philos Trans R Soc Lond B Biol Sci},

volume = {375},

number = {1795},

pages = {20190332},

abstract = {Transposable elements (TEs) are increasingly recognized as important contributors to mammalian regulatory systems. For instance, they have been shown to play a role in the human interferon response, but their involvement in other mechanisms of immune cell activation remains poorly understood. Here, we investigated the profile of accessible chromatin enhanced in stimulated human macrophages using ATAC-seq to assess the role of different TE subfamilies in regulating gene expression following an immune response. We found that both previously identified and new repeats belonging to the MER44, THE1, Tigger3 and MLT1 families provide 14 subfamilies that are enriched in differentially accessible chromatin and found near differentially expressed genes. These TEs also harbour binding motifs for several candidate transcription factors, including important immune regulators AP-1 and NF-κB, present in 96% of accessible MER44B and 83% of THE1C instances, respectively. To more directly assess their regulatory potential, we evaluated the presence of these TEs in regions putatively affecting gene expression, as defined by quantitative trait locus (QTL) analysis, and found that repeats are also contributing to accessible elements near QTLs. Together, these results suggest that a number of TE families have contributed to the regulation of gene expression in the context of the immune response to infection in humans. This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32025003b,

title = {Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing},

author = {Isidro Cortés-Ciriano and Jake June-Koo Lee and Ruibin Xi and Dhawal Jain and Youngsook L Jung and Lixing Yang and Dmitry Gordenin and Leszek J Klimczak and Cheng-Zhong Zhang and David S Pellman and  and Peter J Park and },

doi = {10.1038/s41588-019-0576-7},

issn = {1546-1718},

year  = {2020},

date = {2020-03-01},

journal = {Nat Genet},

volume = {52},

number = {3},

pages = {331--341},

abstract = {Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32025001b,

title = {The landscape of viral associations in human cancers},

author = {Marc Zapatka and Ivan Borozan and Daniel S Brewer and Murat Iskar and Adam Grundhoff and Malik Alawi and Nikita Desai and Holger Sültmann and Holger Moch and  and Colin S Cooper and Roland Eils and Vincent Ferretti and Peter Lichter and },

doi = {10.1038/s41588-019-0558-9},

issn = {1546-1718},

year  = {2020},

date = {2020-03-01},

journal = {Nat Genet},

volume = {52},

number = {3},

pages = {320--330},

abstract = {Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024999b,

title = {Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer},

author = {Kadir C Akdemir and Victoria T Le and Sahaana Chandran and Yilong Li and Roel G Verhaak and Rameen Beroukhim and Peter J Campbell and Lynda Chin and Jesse R Dixon and P Andrew Futreal and  and },

doi = {10.1038/s41588-019-0564-y},

issn = {1546-1718},

year  = {2020},

date = {2020-03-01},

journal = {Nat Genet},

volume = {52},

number = {3},

pages = {294--305},

abstract = {Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024998b,

title = {Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition},

author = {Bernardo Rodriguez-Martin and Eva G Alvarez and Adrian Baez-Ortega and Jorge Zamora and Fran Supek and Jonas Demeulemeester and Martin Santamarina and Young Seok Ju and Javier Temes and Daniel Garcia-Souto and Harald Detering and Yilong Li and Jorge Rodriguez-Castro and Ana Dueso-Barroso and Alicia L Bruzos and Stefan C Dentro and Miguel G Blanco and Gianmarco Contino and Daniel Ardeljan and Marta Tojo and Nicola D Roberts and Sonia Zumalave and Paul A Edwards and Joachim Weischenfeldt and Montserrat Puiggròs and Zechen Chong and Ken Chen and Eunjung Alice Lee and Jeremiah A Wala and Keiran M Raine and Adam Butler and Sebastian M Waszak and Fabio C P Navarro and Steven E Schumacher and Jean Monlong and Francesco Maura and Niccolo Bolli and Guillaume Bourque and Mark Gerstein and Peter J Park and David C Wedge and Rameen Beroukhim and David Torrents and Jan O Korbel and Iñigo Martincorena and Rebecca C Fitzgerald and Peter Van Loo and Haig H Kazazian and Kathleen H Burns and  and Peter J Campbell and Jose M C Tubio and },

doi = {10.1038/s41588-019-0562-0},

issn = {1546-1718},

year  = {2020},

date = {2020-03-01},

journal = {Nat Genet},

volume = {52},

number = {3},

pages = {306--319},

abstract = {About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024997b,

title = {Comprehensive molecular characterization of mitochondrial genomes in human cancers},

author = {Yuan Yuan and Young Seok Ju and Youngwook Kim and Jun Li and Yumeng Wang and Christopher J Yoon and Yang Yang and Inigo Martincorena and Chad J Creighton and John N Weinstein and Yanxun Xu and Leng Han and Hyung-Lae Kim and Hidewaki Nakagawa and Keunchil Park and Peter J Campbell and Han Liang and },

doi = {10.1038/s41588-019-0557-x},

issn = {1546-1718},

year  = {2020},

date = {2020-03-01},

journal = {Nat Genet},

volume = {52},

number = {3},

pages = {342--352},

abstract = {Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024987b,

title = {Butler enables rapid cloud-based analysis of thousands of human genomes},

author = {Sergei Yakneen and Sebastian M Waszak and  and Michael Gertz and Jan O Korbel and },

doi = {10.1038/s41587-019-0360-3},

issn = {1546-1696},

year  = {2020},

date = {2020-03-01},

journal = {Nat Biotechnol},

volume = {38},

number = {3},

pages = {288--292},

abstract = {We present Butler, a computational tool that facilitates large-scale genomic analyses on public and academic clouds. Butler includes innovative anomaly detection and self-healing functions that improve the efficiency of data processing and analysis by 43% compared with current approaches. Butler enabled processing of a 725-terabyte cancer genome dataset from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project in a time-efficient and uniform manner.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32025019b,

title = {Genomic basis for RNA alterations in cancer},

author = { and Claudia Calabrese and Natalie R Davidson and Deniz Demircioğlu and Nuno A Fonseca and Yao He and André Kahles and Kjong-Van Lehmann and Fenglin Liu and Yuichi Shiraishi and Cameron M Soulette and Lara Urban and Liliana Greger and Siliang Li and Dongbing Liu and Marc D Perry and Qian Xiang and Fan Zhang and Junjun Zhang and Peter Bailey and Serap Erkek and Katherine A Hoadley and Yong Hou and Matthew R Huska and Helena Kilpinen and Jan O Korbel and Maximillian G Marin and Julia Markowski and Tannistha Nandi and Qiang Pan-Hammarström and Chandra Sekhar Pedamallu and Reiner Siebert and Stefan G Stark and Hong Su and Patrick Tan and Sebastian M Waszak and Christina Yung and Shida Zhu and Philip Awadalla and Chad J Creighton and Matthew Meyerson and B F Francis Ouellette and Kui Wu and Huanming Yang and  and Alvis Brazma and Angela N Brooks and Jonathan Göke and Gunnar Rätsch and Roland F Schwarz and Oliver Stegle and Zemin Zhang and },

doi = {10.1038/s41586-020-1970-0},

issn = {1476-4687},

year  = {2020},

date = {2020-02-01},

journal = {Nature},

volume = {578},

number = {7793},

pages = {129--136},

abstract = {Transcript alterations often result from somatic changes in cancer genomes. Various forms of RNA alterations have been described in cancer, including overexpression, altered splicing and gene fusions; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32025018b,

title = {The repertoire of mutational signatures in human cancer},

author = {Ludmil B Alexandrov and Jaegil Kim and Nicholas J Haradhvala and Mi Ni Huang and Alvin Wei Tian Ng and Yang Wu and Arnoud Boot and Kyle R Covington and Dmitry A Gordenin and Erik N Bergstrom and S M Ashiqul Islam and Nuria Lopez-Bigas and Leszek J Klimczak and John R McPherson and Sandro Morganella and Radhakrishnan Sabarinathan and David A Wheeler and Ville Mustonen and  and Gad Getz and Steven G Rozen and Michael R Stratton and },

doi = {10.1038/s41586-020-1943-3},

issn = {1476-4687},

year  = {2020},

date = {2020-02-01},

journal = {Nature},

volume = {578},

number = {7793},

pages = {94--101},

abstract = {Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32025015b,

title = {Analyses of non-coding somatic drivers in 2,658 cancer whole genomes},

author = {Esther Rheinbay and Morten Muhlig Nielsen and Federico Abascal and Jeremiah A Wala and Ofer Shapira and Grace Tiao and Henrik Hornshøj and Julian M Hess and Randi Istrup Juul and Ziao Lin and Lars Feuerbach and Radhakrishnan Sabarinathan and Tobias Madsen and Jaegil Kim and Loris Mularoni and Shimin Shuai and Andrés Lanzós and Carl Herrmann and Yosef E Maruvka and Ciyue Shen and Samirkumar B Amin and Pratiti Bandopadhayay and Johanna Bertl and Keith A Boroevich and John Busanovich and Joana Carlevaro-Fita and Dimple Chakravarty and Calvin Wing Yiu Chan and David Craft and Priyanka Dhingra and Klev Diamanti and Nuno A Fonseca and Abel Gonzalez-Perez and Qianyun Guo and Mark P Hamilton and Nicholas J Haradhvala and Chen Hong and Keren Isaev and Todd A Johnson and Malene Juul and Andre Kahles and Abdullah Kahraman and Youngwook Kim and Jan Komorowski and Kiran Kumar and Sushant Kumar and Donghoon Lee and Kjong-Van Lehmann and Yilong Li and Eric Minwei Liu and Lucas Lochovsky and Keunchil Park and Oriol Pich and Nicola D Roberts and Gordon Saksena and Steven E Schumacher and Nikos Sidiropoulos and Lina Sieverling and Nasa Sinnott-Armstrong and Chip Stewart and David Tamborero and Jose M C Tubio and Husen M Umer and Liis Uusküla-Reimand and Claes Wadelius and Lina Wadi and Xiaotong Yao and Cheng-Zhong Zhang and Jing Zhang and James E Haber and Asger Hobolth and Marcin Imielinski and Manolis Kellis and Michael S Lawrence and Christian von Mering and Hidewaki Nakagawa and Benjamin J Raphael and Mark A Rubin and Chris Sander and Lincoln D Stein and Joshua M Stuart and Tatsuhiko Tsunoda and David A Wheeler and Rory Johnson and Jüri Reimand and Mark Gerstein and Ekta Khurana and Peter J Campbell and Núria López-Bigas and  and  and Joachim Weischenfeldt and Rameen Beroukhim and Iñigo Martincorena and Jakob Skou Pedersen and Gad Getz and },

doi = {10.1038/s41586-020-1965-x},

issn = {1476-4687},

year  = {2020},

date = {2020-02-01},

journal = {Nature},

volume = {578},

number = {7793},

pages = {102--111},

abstract = {The discovery of drivers of cancer has traditionally focused on protein-coding genes. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32025013b,

title = {The evolutionary history of 2,658 cancers},

author = {Moritz Gerstung and Clemency Jolly and Ignaty Leshchiner and Stefan C Dentro and Santiago Gonzalez and Daniel Rosebrock and Thomas J Mitchell and Yulia Rubanova and Pavana Anur and Kaixian Yu and Maxime Tarabichi and Amit Deshwar and Jeff Wintersinger and Kortine Kleinheinz and Ignacio Vázquez-García and Kerstin Haase and Lara Jerman and Subhajit Sengupta and Geoff Macintyre and Salem Malikic and Nilgun Donmez and Dimitri G Livitz and Marek Cmero and Jonas Demeulemeester and Steven Schumacher and Yu Fan and Xiaotong Yao and Juhee Lee and Matthias Schlesner and Paul C Boutros and David D Bowtell and Hongtu Zhu and Gad Getz and Marcin Imielinski and Rameen Beroukhim and S Cenk Sahinalp and Yuan Ji and Martin Peifer and Florian Markowetz and Ville Mustonen and Ke Yuan and Wenyi Wang and Quaid D Morris and  and Paul T Spellman and David C Wedge and Peter Van Loo and },

doi = {10.1038/s41586-019-1907-7},

issn = {1476-4687},

year  = {2020},

date = {2020-02-01},

journal = {Nature},

volume = {578},

number = {7793},

pages = {122--128},

abstract = {Cancer develops through a process of somatic evolution. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32025012b,

title = {Patterns of somatic structural variation in human cancer genomes},

author = {Yilong Li and Nicola D Roberts and Jeremiah A Wala and Ofer Shapira and Steven E Schumacher and Kiran Kumar and Ekta Khurana and Sebastian Waszak and Jan O Korbel and James E Haber and Marcin Imielinski and  and Joachim Weischenfeldt and Rameen Beroukhim and Peter J Campbell and },

doi = {10.1038/s41586-019-1913-9},

issn = {1476-4687},

year  = {2020},

date = {2020-02-01},

journal = {Nature},

volume = {578},

number = {7793},

pages = {112--121},

abstract = {A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions-as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and-in liver cancer-frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32025007b,

title = {Pan-cancer analysis of whole genomes},

author = { },

doi = {10.1038/s41586-020-1969-6},

issn = {1476-4687},

year  = {2020},

date = {2020-02-01},

journal = {Nature},

volume = {578},

number = {7793},

pages = {82--93},

abstract = {Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024996b,

title = {Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis},

author = {Joana Carlevaro-Fita and Andrés Lanzós and Lars Feuerbach and Chen Hong and David Mas-Ponte and Jakob Skou Pedersen and  and Rory Johnson and },

doi = {10.1038/s42003-019-0741-7},

issn = {2399-3642},

year  = {2020},

date = {2020-02-01},

journal = {Commun Biol},

volume = {3},

number = {1},

pages = {56},

abstract = {Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024854b,

title = {Pathway and network analysis of more than 2500 whole cancer genomes},

author = {Matthew A Reyna and David Haan and Marta Paczkowska and Lieven P C Verbeke and Miguel Vazquez and Abdullah Kahraman and Sergio Pulido-Tamayo and Jonathan Barenboim and Lina Wadi and Priyanka Dhingra and Raunak Shrestha and Gad Getz and Michael S Lawrence and Jakob Skou Pedersen and Mark A Rubin and David A Wheeler and Søren Brunak and Jose M G Izarzugaza and Ekta Khurana and Kathleen Marchal and Christian von Mering and S Cenk Sahinalp and Alfonso Valencia and  and Jüri Reimand and Joshua M Stuart and Benjamin J Raphael and },

doi = {10.1038/s41467-020-14367-0},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {729},

abstract = {The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024849b,

title = {A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns},

author = {Wei Jiao and Gurnit Atwal and Paz Polak and Rosa Karlic and Edwin Cuppen and  and Alexandra Danyi and Jeroen de Ridder and Carla van Herpen and Martijn P Lolkema and Neeltje Steeghs and Gad Getz and Quaid D Morris and Lincoln D Stein and },

doi = {10.1038/s41467-019-13825-8},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {728},

abstract = {In cancer, the primary tumour's organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024846b,

title = {Integrative pathway enrichment analysis of multivariate omics data},

author = {Marta Paczkowska and Jonathan Barenboim and Nardnisa Sintupisut and Natalie S Fox and Helen Zhu and Diala Abd-Rabbo and Miles W Mee and Paul C Boutros and  and Jüri Reimand and },

doi = {10.1038/s41467-019-13983-9},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {735},

abstract = {Multi-omics datasets represent distinct aspects of the central dogma of molecular biology. Such high-dimensional molecular profiles pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple datasets using statistical data fusion, rationalizes contributing evidence and highlights associated genes. As part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we integrated genes with coding and non-coding mutations and revealed frequently mutated pathways and additional cancer genes with infrequent mutations. We also analyzed prognostic molecular pathways by integrating genomic and transcriptomic features of 1780 breast cancers and highlighted associations with immune response and anti-apoptotic signaling. Integration of ChIP-seq and RNA-seq data for master regulators of the Hippo pathway across normal human tissues identified processes of tissue regeneration and stem cell regulation. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024845b,

title = {Inferring structural variant cancer cell fraction},

author = {Marek Cmero and Ke Yuan and Cheng Soon Ong and Jan Schröder and  and Niall M Corcoran and Tony Papenfuss and Christopher M Hovens and Florian Markowetz and Geoff Macintyre and },

doi = {10.1038/s41467-020-14351-8},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {730},

abstract = {We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines the variant allele frequencies of both SV breakends, then simultaneously estimates the cancer cell fraction and SV copy number. We assess performance using in silico mixtures of real samples, at known proportions, created from two clonal metastases from the same patient. We find that SVclone's performance is comparable to single-nucleotide variant-based methods, despite having an order of magnitude fewer data points. As part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we use SVclone to reveal a subset of liver, ovarian and pancreatic cancers with subclonally enriched copy-number neutral rearrangements that show decreased overall survival. SVclone enables improved characterisation of SV intra-tumour heterogeneity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024834b,

title = {Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig},

author = {Yulia Rubanova and Ruian Shi and Caitlin F Harrigan and Roujia Li and Jeff Wintersinger and Nil Sahin and Amit G Deshwar and  and Quaid D Morris and },

doi = {10.1038/s41467-020-14352-7},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {731},

abstract = {The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types that co-occur in the same tumours. However, it remains unclear how mutation processes change during cancer evolution due to the lack of reliable methods to reconstruct evolutionary trajectories of mutational signature activity. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we present TrackSig, a new method that reconstructs these trajectories using optimal, joint segmentation and deconvolution of mutation type and allele frequencies from a single tumour sample. In simulations, we find TrackSig has a 3-5% activity reconstruction error, and 12% false detection rate. It outperforms an aggressive baseline in situations with branching evolution, CNA gain, and neutral mutations. Applied to data from 2658 tumours and 38 cancer types, TrackSig permits pan-cancer insight into evolutionary changes in mutational processes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024823b,

title = {High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations},

author = {Yiqun Zhang and Fengju Chen and Nuno A Fonseca and Yao He and Masashi Fujita and Hidewaki Nakagawa and Zemin Zhang and Alvis Brazma and  and  and Chad J Creighton and },

doi = {10.1038/s41467-019-13885-w},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {736},

abstract = {The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024819b,

title = {Divergent mutational processes distinguish hypoxic and normoxic tumours},

author = {Vinayak Bhandari and Constance H Li and Robert G Bristow and Paul C Boutros and },

doi = {10.1038/s41467-019-14052-x},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {737},

abstract = {Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024818b,

title = {Combined burden and functional impact tests for cancer driver discovery using DriverPower},

author = {Shimin Shuai and  and Steven Gallinger and Lincoln D Stein and },

doi = {10.1038/s41467-019-13929-1},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {734},

abstract = {The discovery of driver mutations is one of the key motivations for cancer genome sequencing. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify driver mutations in coding and non-coding sites within cancer whole genomes. Using a total of 1373 genomic features derived from public sources, DriverPower's background mutation model explains up to 93% of the regional variance in the mutation rate across multiple tumour types. By incorporating functional impact scores, we are able to further increase the accuracy of driver discovery. Testing across a collection of 2583 cancer genomes from the PCAWG project, DriverPower identifies 217 coding and 95 non-coding driver candidates. Comparing to six published methods used by the PCAWG Drivers and Functional Interpretation Working Group, DriverPower has the highest F1 score for both coding and non-coding driver discovery. This demonstrates that DriverPower is an effective framework for computational driver discovery.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32024817b,

title = {Genomic footprints of activated telomere maintenance mechanisms in cancer},

author = {Lina Sieverling and Chen Hong and Sandra D Koser and Philip Ginsbach and Kortine Kleinheinz and Barbara Hutter and Delia M Braun and Isidro Cortés-Ciriano and Ruibin Xi and Rolf Kabbe and Peter J Park and Roland Eils and Matthias Schlesner and  and Benedikt Brors and Karsten Rippe and David T W Jones and Lars Feuerbach and },

doi = {10.1038/s41467-019-13824-9},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {733},

abstract = {Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXX) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXX tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31591503b,

title = {A point mutation in the linker domain of mouse STAT5A is associated with impaired NK-cell regulation},

author = {Salma Chehboun and Gabriel André Leiva-Torres and Benoît Charbonneau and Robert Eveleigh and Guillaume Bourque and Silvia Marina Vidal},

doi = {10.1038/s41435-019-0088-6},

issn = {1476-5470},

year  = {2020},

date = {2020-02-01},

journal = {Genes Immun},

volume = {21},

number = {2},

pages = {136--141},

abstract = {The transcription factor STAT5 is critical for peripheral NK-cell survival, proliferation, and cytotoxic function. STAT5 refers to two highly related proteins, STAT5A and STAT5B. In this study, we verified the importance of STAT5A isoform for NK cells. We characterized an incidental chemically induced W484G mutation in the Stat5a gene and found that this mutation was associated with a reduction of STAT5A protein expression. Closer examination of NK-cell subsets from Stat5a mutant mice showed marked reductions in NK-cell number and maturation. IL-15 treatment of Stat5a mutant NK cells exhibited defective induction of both STAT5 and mTOR signaling pathways and reduced expression of granzyme B and IFN-γ. Finally, we observed that Stat5a mutant mice revealed more tumor growth upon injection of RMA-S tumor cell line. Overall, our results demonstrate that the W484G mutation in the linker domain of STAT5A is sufficient to compromise STAT5A function in NK-cell homeostasis, responsiveness, and tumoricidal function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{chehboun_point_2020b,

title = {A point mutation in the linker domain of mouse STAT5A is associated with impaired NK-cell regulation},

author = {Salma Chehboun and Gabriel André Leiva-Torres and Benoît Charbonneau and Robert Eveleigh and Guillaume Bourque and Silvia Marina Vidal},

url = {https://www.nature.com/articles/s41435-019-0088-6},

doi = {10.1038/s41435-019-0088-6},

issn = {1476-5470},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {Genes & Immunity},

volume = {21},

number = {2},

pages = {136--141},

abstract = {The transcription factor STAT5 is critical for peripheral NK-cell survival, proliferation, and cytotoxic function. STAT5 refers to two highly related proteins, STAT5A and STAT5B. In this study, we verified the importance of STAT5A isoform for NK cells. We characterized an incidental chemically induced W484G mutation in the Stat5a gene and found that this mutation was associated with a reduction of STAT5A protein expression. Closer examination of NK-cell subsets from Stat5a mutant mice showed marked reductions in NK-cell number and maturation. IL-15 treatment of Stat5a mutant NK cells exhibited defective induction of both STAT5 and mTOR signaling pathways and reduced expression of granzyme B and IFN-γ. Finally, we observed that Stat5a mutant mice revealed more tumor growth upon injection of RMA-S tumor cell line. Overall, our results demonstrate that the W484G mutation in the linker domain of STAT5A is sufficient to compromise STAT5A function in NK-cell homeostasis, responsiveness, and tumoricidal function.},

note = {Number: 2 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{brereton_co-cropping_2020,

title = {Co-cropping with three phytoremediation crops influences rhizosphere microbiome community in contaminated soil},

author = {N J B Brereton and E Gonzalez and D Desjardins and M Labrecque and F E Pitre},

url = {https://www.sciencedirect.com/science/article/pii/S0048969719350594},

doi = {10.1016/j.scitotenv.2019.135067},

issn = {0048-9697},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {Science of The Total Environment},

volume = {711},

pages = {135067},

abstract = {Human industrial activities have left millions of hectares of land polluted with trace element metals and persistent organic pollutants (POPs) around the world. Although contaminated sites are environmentally damaging, high economic costs often discourage soil remediation efforts. Phytoremediation is a potential green technology solution but can be challenging due to the diversity of anthropogenic contaminants. Co-cropping could provide improved tolerance to diverse soil challenges by taking advantage of distinct crop capabilities. Co-cropping of three species with potentially complementary functions, Festuca arundinacea, Salix miyabeana and Medicago sativa, perform well on diversely contaminated soils. Here, rhizosphere microbiomes of each crop in monoculture and in all co-cropping combinations were compared using 16S rRNA gene amplification, sequencing and differential abundance analysis. The hyperaccumulating F. arundinacea rhizosphere microbiome included putative plant growth promoting bacteria (PGPB) and metal tolerance species, such as Rhizorhapis suberifaciens, Cellvibrio fibrivorans and Pseudomonas lini. The rhizosphere microbiome of the fast-growing tree S. miyabeana included diverse taxa involved in POP degradation, including the species Phenylobacterium panacis. The well-characterised nitrogen-fixing M. sativa microbiome species, Sinorhizobium meliloti, was identified alongside others involved in nutrient acquisition and putative yet-to-be-cultured Candidatus saccharibacteria (TM7-1 group). The majority of differentially abundant rhizosphere-associated bacterial species were maintained in co-cropping pairs, with pairs having higher numbers of differentially abundant taxa than monocultures in all cases. This was not the case when all three crops were co-cropped, where most host-specific bacterial species were not detected as differentially abundant, indicating the potential for reduced rhizosphere functionality. The crops cultivated in pairs here retained rhizosphere microbiome bacteria involved in these monoculture ecosystem services of plant growth promotion, POP tolerance and degradation, and improved nutrient acquisition. These findings provide a promising outlook of the potential for complementary co-cropping strategies for phytoremediation of the multifaceted anthropogenic pollution which can disastrously affect soils around the world.},

keywords = {16S rRNA, Co-cropping, Metagenomics, Microbiome, Phytoremediation, Rhizosphere},

pubstate = {published},

tppubtype = {article}

}

@article{nikbakht_latency_2020,

title = {Latency and interval therapy affect the evolution in metastatic colorectal cancer},

author = {Hamid Nikbakht and Selin Jessa and Mahadeo A Sukhai and Madeleine Arseneault and Tong Zhang and Louis Letourneau and Mariam Thomas and Mathieu Bourgey and Michael H A Roehrl and Robert Eveleigh and Eric X Chen and Monika Krzyzanowska and Malcolm J Moore and Amanda Giesler and Celeste Yu and Philippe L Bedard and Suzanne Kamel-Reid and Jacek Majewski and Lillian L Siu and Yasser Riazalhosseini and Donna M Graham},

url = {https://www.nature.com/articles/s41598-020-57476-y},

doi = {10.1038/s41598-020-57476-y},

issn = {2045-2322},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {Scientific Reports},

volume = {10},

number = {1},

pages = {581},

abstract = {While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g., those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of latency in the evolutionary path of metastatic CRC and may have implications for future treatment options.},

note = {Number: 1 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lee_characterization_2020,

title = {Characterization of Growth Morphology and Pathology, and Draft Genome Sequencing of Botrytis fabae, the Causal Organism of Chocolate Spot of Faba Bean (Vicia faba L.)},

author = {Robert C Lee and Lina M Farfan-Caceres and Johannes W Debler and Robert A Syme},

url = {https://www.frontiersin.org/articles/10.3389/fmicb.2020.00217/full},

doi = {10.3389/fmicb.2020.00217},

issn = {1664-302X},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {Frontiers in Microbiology},

volume = {11},

abstract = {Abstract Chocolate spot is a major fungal disease of faba bean caused by the ascomycete fungus, Botrytis fabae. B. fabae is also implicated in botrytis grey mould disease in lentils, along with B. cinerea. Here we have isolated and characterised two B. fabae isolates from chocolate spot lesions on faba bean leaves. In plant disease assays on faba bean and lentil, B. fabae was more aggressive than B. cinerea and we observed variation in susceptibility among a small set of cultivars for both plant hosts. Using light microscopy, we observed a spreading, generalised necrosis response in faba bean towards B. fabae. In contrast, the plant response to B. cinerea was localised to epidermal cells underlying germinated spores and appressoria. In addition to the species characterisation of B. fabae, we produced genome assemblies for both B. fabae isolates using Illumina sequencing. Genome sequencing coverage and assembly size for B. fabae isolates, were 27x and 45x, and 43.2 Mb and 44.5 Mb, respectively. Following genome assembly and annotation, carbohydrate-active enzyme (CAZymes) and effector genes were predicted. There were no major differences in the numbers of each of the major classes of CAZymes. We predicted 29 effector genes for B. fabae, and using the same selection criteria for B. cinerea, we predicted 34 putative effector genes. For five of the predicted effector genes, the pairwise dN/dS ratio between orthologs from B. fabae and B. cinerea was greater than 1.0, suggesting positive selection and the potential evolution of molecular mechanisms for host specificity in B. fabae. Furthermore, a homology search of secondary metabolite clusters revealed the absence of the B. cinerea phytotoxin botrydial and several other uncharacterised secondary metabolite biosynthesis genes from B. fabae. Although there were no obvious differences in the number or proportional representation of different transposable element classes, the overall proportion of AT-rich DNA sequence in B. fabae was double that of B. cinerea.},

note = {Publisher: Frontiers},

keywords = {ascomycete, BGM, botrytis fabae, chocolate spot, faba bean, Grey mould, Lens culinaris, Lentil, Necrotroph, phytopathogen, Plant Pathogen, Vicia faba},

pubstate = {published},

tppubtype = {article}

}

@article{morfin_interaction_2020,

title = {Interaction of field realistic doses of clothianidin and Varroa destructor parasitism on adult honey bee (Apis mellifera L.) health and neural gene expression, and antagonistic effects on differentially expressed genes},

author = {Nuria Morfin and Paul H Goodwin and Ernesto Guzman-Novoa},

url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229030},

doi = {10.1371/journal.pone.0229030},

issn = {1932-6203},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {PLOS ONE},

volume = {15},

number = {2},

pages = {e0229030},

abstract = {While many studies have examined the effects of neonicotinoid insecticides and the parasitic mite Varroa destructor on honey bees (Apis mellifera), more information on the combined effects of such stressors on gene expression, including neural related genes, and their impact on biological pathways is needed. This study analyzed the effects of field realistic concentrations of the neonicotinoid clothianidin on adult bees infested and not infested with V. destructor over 21 consecutive days and then determined bee survivorship, weight, deformed wing virus (DWV) levels and gene expression. V. destructor parasitism with or without clothianidin exposure was significantly associated with decreased survivorship, weight loss and higher DWV levels, while clothianidin exposure was only associated with higher levels of DWV. Expression analysis of the neural genes AmNlg-1, BlCh and AmAChE-2 showed that V. destructor caused a significant down-regulation of all of them, whereas clothianidin caused a significant down-regulation of only AmNrx-1 and BlCh. An interaction was only detected for AmNrx-1 expression. RNAseq analysis showed that clothianidin exposure resulted in 6.5 times more up-regulated differentially expressed genes (DEGs) than V. destructor alone and 123 times more than clothianidin combined with V. destructor. Similar results were obtained with down-regulated DEGs, except for a higher number of DEGs shared between V. destructor and the combined stressors. KEGG (Kyoto Encyclopedia of Genes and Genomes) biological pathway analysis of the DEGs showed that the stressor linked to the highest number of KEGG pathways was clothianidin, followed by V. destructor, and then considerably fewer number of KEGG pathways with the combined stressors. The reduced numbers of DEGs and KEGG pathways associated with the DEGs for the combined stressors compared to the stressors alone indicates that the interaction of the stressors is not additive or synergistic, but antagonistic. The possible implications of the antagonistic effect on the number of DEGs are discussed.},

note = {Publisher: Public Library of Science},

keywords = {Bees, Behavior, Gene expression, Honey bees, Insecticides, Invertebrate genomics, Mites, Parasitism},

pubstate = {published},

tppubtype = {article}

}

@article{el-sehemy_norrin_2020,

title = {Norrin mediates tumor-promoting and -suppressive effects in glioblastoma via Notch and Wnt},

author = {Ahmed El-Sehemy and Hayden Selvadurai and Arturo Ortin-Martinez and Neno Pokrajac and Yasin Mamatjan and Nobuhiko Tachibana and Katherine Rowland and Lilian Lee and Nicole Park and Kenneth Aldape and Peter Dirks and Valerie A Wallace},

url = {https://www.jci.org/articles/view/128994},

doi = {10.1172/JCI128994},

issn = {0021-9738},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {The Journal of Clinical Investigation},

volume = {130},

number = {6},

pages = {3069--3086},

note = {Publisher: American Society for Clinical Investigation},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{moolhuijzen_expansion_2020,

title = {Expansion and Conservation of Biosynthetic Gene Clusters in Pathogenic Pyrenophora spp.},

author = {Paula M Moolhuijzen and Mariano Jordi Muria-Gonzalez and Robert Syme and Catherine Rawlinson and Pao Theen See and Caroline S Moffat and Simon R Ellwood},

url = {https://www.mdpi.com/2072-6651/12/4/242},

doi = {10.3390/toxins12040242},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {Toxins},

volume = {12},

number = {4},

pages = {242},

abstract = {Pyrenophora is a fungal genus responsible for a number of major cereal diseases. Although fungi produce many specialised or secondary metabolites for defence and interacting with the surrounding environment, the repertoire of specialised metabolites (SM) within Pyrenophora pathogenic species remains mostly uncharted. In this study, an in-depth comparative analysis of the P. teres f. teres, P teres f. maculata and P. tritici-repentis potential to produce SMs, based on in silico predicted biosynthetic gene clusters (BGCs), was conducted using genome assemblies from PacBio DNA reads. Conservation of BGCs between the Pyrenophora species included type I polyketide synthases, terpene synthases and the first reporting of a type III polyketide synthase in P teres f. maculata. P. teres isolates exhibited substantial expansion of non-ribosomal peptide synthases relative to P. tritici-repentis, hallmarked by the presence of tailoring cis-acting nitrogen methyltransferase domains. P. teres isolates also possessed unique non-ribosomal peptide synthase (NRPS)-indole and indole BGCs, while a P. tritici-repentis phytotoxin BGC for triticone production was absent in P. teres. These differences highlight diversification between the pathogens that reflects their different evolutionary histories, host adaption and lifestyles.},

note = {Number: 4 

Publisher: Multidisciplinary Digital Publishing Institute},

keywords = {comparative genomics, necrotrophic fungal pathogen, NRPS, PKS, secondary metabolism, synteny},

pubstate = {published},

tppubtype = {article}

}

@article{choufani_dna_2020,

title = {DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes},

author = {Sanaa Choufani and William T Gibson and Andrei L Turinsky and Brian H Y Chung and Tianren Wang and Kopal Garg and Alessandro Vitriolo and Ana S A Cohen and Sharri Cyrus and Sarah Goodman and Eric Chater-Diehl and Jack Brzezinski and Michael Brudno and Luk Ho Ming and Susan M White and Sally Ann Lynch and Carol Clericuzio and Karen I Temple and Frances Flinter and Vivienne McConnell and Tom Cushing and Lynne M Bird and Miranda Splitt and Bronwyn Kerr and Stephen W Scherer and Jerry Machado and Eri Imagawa and Nobuhiko Okamoto and Naomichi Matsumoto and Guiseppe Testa and Maria Iascone and Romano Tenconi and Oana Caluseriu and Roberto Mendoza-Londono and David Chitayat and Cheryl Cytrynbaum and Katrina Tatton-Brown and Rosanna Weksberg},

url = {https://www.cell.com/ajhg/abstract/S0002-9297(20)30084-7},

doi = {10.1016/j.ajhg.2020.03.008},

issn = {0002-9297, 1537-6605},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {The American Journal of Human Genetics},

volume = {106},

number = {5},

pages = {596--610},

note = {Publisher: Elsevier},

keywords = {DNA methylation signature, EED, intellectual disability, overgrowth syndromes, SUZ12},

pubstate = {published},

tppubtype = {article}

}

@article{groza_personalized_2020,

title = {Personalized and graph genomes reveal missing signal in epigenomic data},

author = {Cristian Groza and Tony Kwan and Nicole Soranzo and Tomi Pastinen and Guillaume Bourque},

url = {https://doi.org/10.1186/s13059-020-02038-8},

doi = {10.1186/s13059-020-02038-8},

issn = {1474-760X},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {Genome Biology},

volume = {21},

number = {1},

pages = {124},

abstract = {Epigenomic studies that use next generation sequencing experiments typically rely on the alignment of reads to a reference sequence. However, because of genetic diversity and the diploid nature of the human genome, we hypothesize that using a generic reference could lead to incorrectly mapped reads and bias downstream results.},

keywords = {ChIP-seq, De novo assembly, Epigenomics, Genome graphs, Modified reference, Personalized genomes, Reference bias},

pubstate = {published},

tppubtype = {article}

}

@article{tremblay_dissection_2020,

title = {Dissection of Clinical and Gene Expression Signatures of Familial versus Multifactorial Chylomicronemia},

author = {Karine Tremblay and Daniel Gaudet and Etienne Khoury and Diane Brisson},

url = {https://doi.org/10.1210/jendso/bvaa056},

doi = {10.1210/jendso/bvaa056},

issn = {2472-1972},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {Journal of the Endocrine Society},

volume = {4},

number = {bvaa056},

abstract = {Familial chylomicronemia syndrome (FCS) is a rare disorder associated with chylomicronemia (CM) and an increased risk of pancreatitis. Most individuals with CM do not have FCS but exhibit multifactorial CM (MCM), which differs from FCS in terms of risk and disease management. This study aimed to investigate clinical and gene expression profiles of FCS and MCM patients. Anthropometrics, clinical, and biochemical variables were analyzed in 57 FCS and 353 MCM patients. Gene expression analyses were performed in a subsample of 19 FCS, 28 MCM, and 15 normolipidemic controls. Receiver operating characteristic (ROC) curve analyses were performed to analyze the capacity of variables to discriminate FCS from MCM. Sustained fasting triglycerides ≥20 mmol/L (>15 mmol/L with eruptive xanthomas), history of pancreatitis, poor response to fibrates, diagnosis of CM at childhood, body mass index <22 kg/m2, and delipidated apolipoprotein B or glycerol levels <0.9 g/L and <0.05 mmol/L, respectively, had an area under the ROC curve ≥0.7. Gene expression analyses identified 142 probes differentially expressed in FCS and 32 in MCM compared with controls. Among them, 13 probes are shared between FCS and MCM; 63 are specific to FCS and 2 to MCM. Most FCS-specific or shared biomarkers are involved in inflammatory, immune, circadian, postprandial metabolism, signaling, docking systems, or receptor-mediated clearance mechanisms. This study reveals differential signatures of FCS and MCM. It opens the door to the identification of key mechanisms of CM expression and potential targets for the development of new treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{zhuang_sex_2020,

title = {Sex Chromosomes and Sex Phenotype Contribute to Biased DNA Methylation in Mouse Liver},

author = {Qinwei Kim-Wee Zhuang and Jose Hector Galvez and Qian Xiao and Najla AlOgayil and Jeffrey Hyacinthe and Teruko Taketo and Guillaume Bourque and Anna K Naumova},

url = {https://www.mdpi.com/2073-4409/9/6/1436},

doi = {10.3390/cells9061436},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-26},

journal = {Cells},

volume = {9},

number = {6},

pages = {1436},

abstract = {Sex biases in the genome-wide distribution of DNA methylation and gene expression levels are some of the manifestations of sexual dimorphism in mammals. To advance our understanding of the mechanisms that contribute to sex biases in DNA methylation and gene expression, we conducted whole genome bisulfite sequencing (WGBS) as well as RNA-seq on liver samples from mice with different combinations of sex phenotype and sex-chromosome complement. We compared groups of animals with different sex phenotypes, but the same genetic sexes, and vice versa, same sex phenotypes, but different sex-chromosome complements. We also compared sex-biased DNA methylation in mouse and human livers. Our data show that sex phenotype, X-chromosome dosage, and the presence of Y chromosome shape the differences in DNA methylation between males and females. We also demonstrate that sex bias in autosomal methylation is associated with sex bias in gene expression, whereas X-chromosome dosage-dependent methylation differences are not, as expected for a dosage-compensation mechanism. Furthermore, we find partial conservation between the repertoires of mouse and human genes that are associated with sex-biased methylation, an indication that gene function is likely to be an important factor in this phenomenon.},

note = {Number: 6 

Publisher: Multidisciplinary Digital Publishing Institute},

keywords = {DNA methylation, Gene expression, mouse liver, sex-chromosome complement, sexual dimorphism, whole genome bisulfite sequencing},

pubstate = {published},

tppubtype = {article}

}

@article{mohanraj_crescent_2020,

title = {CReSCENT: CanceR Single Cell ExpressioN Toolkit},

author = {Suluxan Mohanraj and Javier J Díaz-Mejía and Martin D Pham and Hillary Elrick and Mia Husić and Shaikh Rashid and Ping Luo and Prabnur Bal and Kevin Lu and Samarth Patel and Alaina Mahalanabis and Alaine Naidas and Erik Christensen and Danielle Croucher and Laura M Richards and Parisa Shooshtari and Michael Brudno and Arun K Ramani and Trevor J Pugh},

url = {https://doi.org/10.1093/nar/gkaa437},

doi = {10.1093/nar/gkaa437},

issn = {0305-1048},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-28},

journal = {Nucleic Acids Research},

volume = {48},

number = {W1},

pages = {W372--W379},

abstract = {CReSCENT: CanceR Single Cell ExpressioN Toolkit (https://crescent.cloud), is an intuitive and scalable web portal incorporating a containerized pipeline execution engine for standardized analysis of single-cell RNA sequencing (scRNA-seq) data. While scRNA-seq data for tumour specimens are readily generated, subsequent analysis requires high-performance computing infrastructure and user expertise to build analysis pipelines and tailor interpretation for cancer biology. CReSCENT uses public data sets and preconfigured pipelines that are accessible to computational biology non-experts and are user-editable to allow optimization, comparison, and reanalysis for specific experiments. Users can also upload their own scRNA-seq data for analysis and results can be kept private or shared with other users.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{couturier_single-cell_2020,

title = {Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy},

author = {Charles P Couturier and Shamini Ayyadhury and Phuong U Le and Javad Nadaf and Jean Monlong and Gabriele Riva and Redouane Allache and Salma Baig and Xiaohua Yan and Mathieu Bourgey and Changseok Lee and Yu Chang David Wang and V Wee Yong and Marie-Christine Guiot and Hamed Najafabadi and Bratislav Misic and Jack Antel and Guillaume Bourque and Jiannis Ragoussis and Kevin Petrecca},

url = {https://www.nature.com/articles/s41467-020-17186-5},

doi = {10.1038/s41467-020-17186-5},

issn = {2041-1723},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-28},

journal = {Nature Communications},

volume = {11},

number = {1},

pages = {3406},

abstract = {Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer’s cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.},

note = {Number: 1 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}