Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: 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

Machine learning-assisted prediction of structure and function of cystine-stabilized peptides and optimization of expression in an E. coli system.

Cystine-stabilized peptides are promising prospects for the pharmaceutical industry as biologics. These peptides carry out a variety of useful functions which could be exploited to treat diseases and kill unwanted organisms. As well, an array of disulfide bonds makes the peptides highly stable against temperature, enzymatic degradation, pH and other adverse physiological conditions. There is a vast number of cystine-stabilized peptides serving as antimicrobial peptides, immunological modulators, ion channel blockers and other functions across a wide array of taxa, from fungi and bacteria to plants and humans. Practical access to these promising bioactive molecules could be greatly accelerated if it were possible to efficiently mine cystine-stabilized peptide sequences from genomic databases, determine the function and structure of each candidate from only the primary sequence, and then express the top candidates in E. coli for biological analysis. In this way, only the natural, presumably functional, variants of a particular family of cystine-stabilized peptides could be collected in large quantities. Going further, it would be desirable to convert the nonspecific activity of antimicrobial peptides to a specific activity, targeting a specific pathogen and leaving the rest of the microbiome intact; in essence, developing a targeted antibiotic. To contribute to developing this pipeline, I developed the machine learningassisted algorithms PredSTP and CSPred to predict structural and functional characteristics, respectively, of cystine-stabilized peptides from primary sequence data. In addition, I developed an E. coli-based expression system for high yield production of recombinant antimicrobial peptides specifically targeted to Staphylococcus aureus. These techniques are now available to collect large libraries of cysteine-stabilized peptide sequences, to express top candidates in E. coli, and to target the peptides to specific pathogens

Classes, Databases, and Prediction Methods of Pharmaceutically and Commercially Important Cystine-Stabilized Peptides

Cystine-stabilized peptides represent a large family of peptides characterized by high structural stability and bactericidal, fungicidal, or insecticidal properties. Found throughout a wide range of taxa, this broad and functionally important family can be subclassified into distinct groups dependent upon their number and type of cystine bonding patters, tertiary structures, and/or their species of origin. Furthermore, the annotation of proteins related to the cystine-stabilized family are under-represented in the literature due to their difficulty of isolation and identification. As a result, there are several recent attempts to collate them into data resources and build analytic tools for their dynamic prediction. Ultimately, the identification and delivery of new members of this family will lead to their growing inclusion into the repertoire of commercial viable alternatives to antibiotics and environmentally safe insecticides. This review of the literature and current state of cystine-stabilized peptide biology is aimed to better describe peptide subfamilies, identify databases and analytics resources associated with specific cystine-stabilized peptides, and highlight their current commercial success

Antipyretic and hepatoprotective potential of Tinospora crispa and investigation of possible lead compounds through in silico approaches

This research describes an investigation of the antipyretic and hepatoprotective properties of both a crude organic extract and various subfractions of the ethnomedicinal plant Tinospora crispa, using appropriate animal models. In an attempt to identify potential lead hepatoprotective compounds, in silico experiments were utilized. Antipyretic activity was assessed via the Brewer's yeast-induced pyrexia method, while hepatoprotective effects were evaluated in a carbon tetrachloride (CCl4)-induced animal model. A computer-aided prediction of activity spectra for substances (PASS) model was applied to a selection of documented phytoconstituents, with the aim of identifying those compounds with most promising hepatoprotective effects. Results were analyzed using Molinspiration software. Our results showed that both the methanol extract (METC) and various subfractions (pet ether, PEFTC; n-hexane, NHFTC; and chloroform, CFTC) significantly (p &lt; .05) reduced pyrexia in a dose-dependent manner. In CCl4-induced hepatotoxicity studies, METC ameliorated elevated hepatic markers including serum alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), and total bilirubin. Malondialdehyde (MDA) levels were significantly reduced, while superoxide dismutase (SOD) levels were significantly increased. Among a selection of metabolites of T. crispa, genkwanin was found to be the most potent hepatoprotective constituent using PASS predictive models. These results demonstrate that both the methanolic extract of T. crispa and those fractions containing genkwanin may offer promise in reducing pyrexia and as a source of potential hepatoprotective agents

Signatures of copy number alterations in human cancer

The gains and losses of DNA that emerge as a consequence of mitotic errors and chromosomal instability are prevalent in cancer. These copy number alterations contribute to cancer initiaition, progression and therapeutic resistance. Here, we present a conceptual framework for examining the patterns of copy number alterations in human cancer using whole-genome sequencing, whole-exome sequencing, and SNP6 microarray data making it widely applicable to diverse datasets. Deploying this framework to 9,873 cancers representing 33 human cancer types from the TCGA project revealed a set of 19 copy number signatures that explain the copy number patterns of 93% of TCGA samples. 15 copy number signatures were attributed to biological processes of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, and chromothripsis. The aetiology of four copy number signatures are unexplained and some cancer types have unique patterns of amplicon signatures associated with extrachromosomal DNA, disease-specific survival, and gains of proto-oncogenes such as MDM2. In contrast to base-scale mutational signatures, no copy number signature associated with known cancer risk factors. The results provide a foundation for exploring patterns of copy number changes in cancer genomes and synthesise the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes giving rise to copy number changes.info:eu-repo/semantics/publishe

Signatures of copy number alterations in human cancer

Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

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.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 (VAFPeer reviewe

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: 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