Daniel Brewer

Daniel Brewer
University of East Anglia | UEA · Norwich Medical School

PhD Computational Biology

About

153
Publications
19,674
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6,550
Citations
Introduction
Daniel Brewer currently works at the Norwich Medical School, University of East Anglia. Daniel does research in Bioinformatics, Biostatistics and Cancer Research.
Additional affiliations
September 2013 - present
University of East Anglia
Position
  • Senior Bioinformatics Officer
January 2006 - August 2013
Institute of Cancer Research
Position
  • Senior Bioinformatician
September 2002 - December 2005
University College London
Position
  • PhD Student

Publications

Publications (153)
Article
Full-text available
Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes...
Article
Full-text available
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing...
Article
Background: Biomarkers are urgently needed to dissect the heterogeneity of prostate cancer between patients to improve treatment and accelerate drug development. We analysed blood mRNA expression arrays to identify patients with metastatic castration-resistant prostate cancer with poorer outcome. Methods: Whole blood was collected into PAXgene t...
Article
Integrated genome-wide screens of DNA copy number and gene expression in human cancers have accelerated the rate of discovery of amplified and overexpressed genes. However, the biological importance of most of the genes identified in such studies remains unclear. In this Analysis, we propose a weight-of-evidence based classification system for iden...
Article
Full-text available
Modern genomics technologies generate huge data sets creating a demand for systems level, experimentally verified, analysis techniques. We examined the transcriptional response to DNA damage in a human T cell line (MOLT4) using microarrays. By measuring both mRNA accumulation and degradation over a short time course, we were able to construct a mec...
Article
Full-text available
The objective is to develop a multivariable risk model for the non-invasive detection of prostate cancer prior to biopsy by integrating information from clinically available parameters, Engrailed-2 (EN2) whole-urine protein levels and data from urinary cell-free RNA. Post-digital-rectal examination urine samples collected as part of the Movember Gl...
Article
Full-text available
The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tumor DNA extracted from blood and...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Full-text available
The highly heterogeneous clinical course of human prostate cancer has prompted the development of multiple RNA biomarkers and diagnostic tools to predict outcome for individual patients. Biomarker discovery is often unstable with, for example, small changes in discovery dataset configuration resulting in large alterations in biomarker composition....
Article
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Unsupervised learning methods, such as Hierarchical Cluster Analysis, are commonly used for the analysis of genomic platform data. Unfortunately, such approaches ignore the well-documented heterogeneous composition of prostate cancer samples. Our aim is to use more sophisticated analytical approaches to deconvolute the structure of prostate cancer...
Article
Full-text available
Background: Prostate cancer exhibits severe clinical heterogeneity and there is a critical need for clinically implementable tools able to precisely and noninvasively identify patients that can either be safely removed from treatment pathways or those requiring further follow up. Our objectives were to develop a multivariable risk prediction model...
Article
Full-text available
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 we...
Article
Full-text available
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. 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...
Article
Full-text available
Purpose: Liquid biopsies that noninvasively detect molecular correlates of aggressive prostate cancer (PCa) could be used to triage patients, reducing the burdens of unnecessary invasive prostate biopsy and enabling early detection of high-risk disease. DNA hypermethylation is among the earliest and most frequent aberrations in PCa. We investigate...
Article
Full-text available
Urine from patients with prostate cancer (PCa) contains gene transcripts that have been used for PCa diagnosis and prognosis. Historically, patient urine samples have been collected after a digital rectal examination of the prostate, which was thought necessary to boost the levels of prostatic secretions in the urine. We herein describe methodology...
Article
Full-text available
Background: Human tissue is increasingly being whole genome sequenced as we transition into an era of genomic medicine. With this arises the potential to detect sequences originating from microorganisms, including pathogens amid the plethora of human sequencing reads. In cancer research, the tumorigenic ability of pathogens is being recognized, fo...
Article
Full-text available
The identification of microbiological infection is usually a diagnostic investigation, a complex process that is firstly initiated by clinical suspicion. With the emergence of high-throughput sequencing (HTS) technologies, metagenomic analysis has unveiled the power to identify microbial DNA/RNA from a diverse range of clinical samples (1). Metagen...
Article
Full-text available
Objectives To develop a risk classifier using urine‐derived extracellular vesicle RNA (UEV‐RNA) capable of providing diagnostic information of disease status prior to biopsy, and prognostic information for men on active surveillance (AS). Patients and Methods Post‐digital rectal examination UEV‐RNA expression profiles from urine (n = 535, multiple...
Article
Full-text available
Sphingosine kinases 1 and 2 (SK1 and SK2) are proto-oncogenic isozymes expressed in many human tumors and associated with chemoresistance and poor prognosis. They are well-recognized therapy targets and their inhibition was shown to induce tumor volume reduction and chemosensitization in multiple cancer models. Oncogenic signaling is extremely comp...
Article
Full-text available
Background Prevention of unnecessary biopsies and overtreatment of indolent disease remains a challenge in the management of prostate cancer. Novel non-invasive tests that can identify clinically significant (intermediate-risk and high-risk) diseases are needed to improve risk stratification and monitoring of prostate cancer patients. Here, we inve...
Preprint
Full-text available
Potential viral pathogens were systematically investigated in the whole-genome and transcriptome sequencing of 2384 donors across Pan-Cancer Analysis of Whole Genomes using a consensus approach integrating three independent pathogen detection pipelines. Viruses were detected in 485 genomic and 70 transcriptome data sets. Besides confirming the prev...
Article
Full-text available
Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previ...
Article
Full-text available
A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss...
Data
Summary characteristics of the genomes and somatic copy number alterations (SCNAs). Left side: Samples classified by disease status i.e. samples from prostatectomies from patients free of metastatic disease (PT) or samples from patients with metastatic disease (M). Right side: Prostatectomy samples where there was at least six months follow up (n =...
Data
Genes with mutations in extended MRA, GISTIC, and homozygous loss regions. Possible haploinsufficiency targets are identified as genes where there are at least three mutations and a normal allele retained. (XLSX)
Data
Copy number alteration segments detected by ASCAT that overlap with deletion MRAs. Each deletion is represented as a distinct colour as shown in the key. Deletions are as follows: neutral LOH (loss of one allele with duplication of the remaining allele); hemizygous deletion LOH (loss of one allele); homozygous loss (loss of the two alleles); and ot...
Data
A platform comparison of ASCAT profiles on a single sample. (a) one profile from SNP6.0 and (b) one from NGS data. (PDF)
Data
Classification of somatic copy number alterations. (DOCX)
Data
Minimal regions of deletions and amplifications with linked genes. This table includes: Comparison of MRAs, extended MRAs and GISTIC-detected regions; amplifications and deletions found in previous prostate cancer studies.; percentage of the minimal regions of alterations that are conserved regions; and clinical correlations and ETS associations of...
Data
Mutations in lncRNAs and conserved RNAs located within the minimal regions of somatic copy number alteration. lncRNAs were examined that were defined by the MiTranscriptome project as being either cancer-associated or containing conserved regions. (XLSX)
Data
GISTIC regions of deletion and amplification. q-values: The q-value of the peak region. Residual q-values: The q-value of the peak region after removing (“peeling off”) amplifications or deletions that overlap other, more significant peak regions in the same chromosome. Wide Peak Limits: The “wide peak” boundaries most likely to contain the targete...
Data
Structural rearrangements in regions of deletion involving genes found to be in or close to minimal regions of alteration. (XLSX)
Data
Structural rearrangements in regions of deletion involving genes found to be in or close to GISTIC detected regions. (XLSX)
Data
Summary of cases and copy number platforms. (DOCX)
Data
Example copy number plots (BAF and logR) for four tumour samples (and associated controls) for each of the 24 novel MCRs that we have identified. The black lines indicate the segment detected by ASCAT and the blue lines indicate the MCR region. (PDF)
Data
Diagrammatic explanation on minimal and extended MRA. (PDF)
Data
Hierarchical clustering of 103 prostate cancer samples with multiscale bootstrap resampling. The data are binary values corresponding to the presence/absence (1/0) of regions of copy number gain and loss in each of the tumour samples. p-values were calculated via hierarchical cluster analysis with multiscale bootstrap resampling of 1000 using Ward’...
Data
Copy number profiling of 103 patients. Including ploidy, degree of contamination and number of SCNAs. Clinico-pathological characteristics of the study cohort consisting of 105 patients. Information on patients undergoing radical prostatectomy (88) and TURP (2) is displayed. (XLSX)
Data
Summary of clinico-pathological characteristics of the patients in the defined sets of clusters. (DOCX)
Data
Mutations in promoter regions of genes within the minimal regions of alteration. (DOCX)
Data
Mutations in DNA High-occupancy target (HOT) regions. (XLSX)
Data
Mutations in conserved DNA sequences within the minimal regions of somatic copy number alteration. (XLSX)
Data
Pathway enrichment analysis of ETS positive and negative cancers using mutated genes in significant regions of amplification and deletion. The analysis was performed using the Reactome plugin for analysis of canonical pathways in Cytoscape. Only significant (FDR calculated using the Benjamini-Hochberg procedure p < 0.05) enriched pathways with pote...
Data
An example statistical consideration of the Knudson 2-hit model. (PDF)
Data
Copy number alteration segments detected by ASCAT that overlap with amplification MRAs. The chromosome gain events are represented with distinct colour blocks depending on the type of SCNA: gain (any gain in the number of normal allele copies) and amplification LOH (loss of one allele with any gain of the remaining allele). The regions of SCNA are...
Data
Commonly altered pathways in ETS positive and negative cancers. Blue and red blocks indicate genes contained in regions of deletion and amplification respectively. Grey blocks indicate genes with no alteration that were required for representation of the pathway. Purple and blue squares indicate the percentage of samples with a copy number alterati...
Data
List of regions of homozygous loss that occur in greater than two patients. (DOCX)
Data
Summary table of the GISTIC detected deletions that follow the Knudson hit model. (DOCX)
Data
Membership of the CRUK-ICGC prostate group. (PDF)
Article
A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss...
Article
Full-text available
Background: A critical problem in the clinical management of prostate cancer is that it is highly heterogeneous. Accurate prediction of individual cancer behaviour is therefore not achievable at the time of diagnosis leading to substantial overtreatment. It remains an enigma that, in contrast to breast cancer, unsupervised analyses of global expre...
Article
Full-text available
\textbf{Background}$: A critical problem in the clinical management of prostate cancer is that it is highly heterogeneous. Accurate prediction of individual cancer behaviour is therefore not achievable at the time of diagnosis leading to substantial overtreatment. It remains an enigma that, in contrast to breast cancer, unsupervised analyses of glo...
Article
Full-text available
Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures...