Showing papers by "Andy G. Lynch published in 2020"
TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
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 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) 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 promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.
1,600 citations
University of Cambridge1, National Institutes of Health2, UCL Institute of Child Health3, Great Ormond Street Hospital for Children NHS Foundation Trust4, NHS Blood and Transplant5, NHS Greater Glasgow and Clyde6, University of Glasgow7, University of Sheffield8, Hull and East Yorkshire Hospitals NHS Trust9, Papworth Hospital10, Boston Children's Hospital11, University of Amsterdam12, Royal Free London NHS Foundation Trust13, University College London14, University of St Andrews15, Oslo University Hospital16, University of Kiel17, University of Oxford18, Trinity College, Dublin19, Salford Royal NHS Foundation Trust20, Imperial College London21, Oxford Health NHS Foundation Trust22, University Hospitals Birmingham NHS Foundation Trust23, University Hospitals of North Midlands NHS Trust24, University Hospital of Wales25, Charité26, Wellcome Trust Sanger Institute27, St James's University Hospital28
TL;DR: Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.
Abstract: Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1,2,3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
105 citations
University of Cambridge1, European Bioinformatics Institute2, Columbia University3, University of Oxford4, Cambridge University Hospitals NHS Foundation Trust5, Salford Royal NHS Foundation Trust6, University of Manchester7, Wigan8, Royal Surrey County Hospital9, Edinburgh Royal Infirmary10, University of Edinburgh11, University Hospitals Birmingham NHS Foundation Trust12, Heart of England NHS Foundation Trust13, University of Birmingham14, University Hospital Southampton NHS Foundation Trust15, University of Southampton16, Karolinska Institutet17, King's College London18, University of Plymouth19, Norfolk and Norwich University Hospital20, Nottingham University Hospitals NHS Trust21, University College London22, Norwich University23, University Hospitals Coventry and Warwickshire NHS Trust24, Peterborough City Hospital25, Imperial College London26, University of Nottingham27, Queen's University Belfast28
TL;DR: In a comprehensive integrated analysis of methylation, transcriptome, and genome profiles of more than 400 BE and EAC tissues, along with clinical data, 4 subtypes were identified that were associated with patient outcomes and potential responses to therapy.
56 citations
TL;DR: This study shows that different handedness measures tap into different dimensions of laterality and cannot be used interchangeably, and sex effects should be taken into account in handedness and laterality studies.
Abstract: The most common way to assess handedness is based on the preferred hand for writing, leading to a binary (left or right) trait. Handedness can also be assessed as a continuous trait with laterality...
21 citations
University of Cambridge1, UCL Institute of Child Health2, University of Glasgow3, NHS Greater Glasgow and Clyde4, University of Sheffield5, Hull and East Yorkshire Hospitals NHS Trust6, Papworth Hospital7, University of Amsterdam8, Great Ormond Street Hospital for Children NHS Foundation Trust9, University College London10, Royal Free London NHS Foundation Trust11, University of St Andrews12, Oslo University Hospital13, University of Kiel14, University of Oxford15, University of Leeds16
TL;DR: A cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening the understanding of the key pathways influencing human immune responsiveness, as well as identifying PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants.
Abstract: Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of - and interplay between - novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
3 citations
University of Cambridge1, National Institutes of Health2, UCL Institute of Child Health3, Great Ormond Street Hospital for Children NHS Foundation Trust4, NHS Blood and Transplant5, University of Glasgow6, NHS Greater Glasgow and Clyde7, University of Sheffield8, Hull and East Yorkshire Hospitals NHS Trust9, Papworth Hospital10, Boston Children's Hospital11, University of Amsterdam12, University College London13, Royal Free London NHS Foundation Trust14, University of St Andrews15, Oslo University Hospital16, University of Kiel17, University of Oxford18, Trinity College, Dublin19, Salford Royal NHS Foundation Trust20, Imperial College London21, Oxford Health NHS Foundation Trust22, University Hospitals Birmingham NHS Foundation Trust23, University Hospitals of North Midlands NHS Trust24, University Hospital of Wales25, Charité26, Wellcome Trust Sanger Institute27, St James's University Hospital28
TL;DR: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
3 citations
TL;DR: Endoscopic morphology may be an important pre-treatment prognostic factor in oesophageal cancer and postoperative survival and demonstrated a significant survival advantage on multivariable analysis.
Abstract: Background Prognostication in oesophageal cancer on the basis of preoperative variables is challenging. Many of the accepted predictors of survival are only derived after surgical treatment and may be influenced by neoadjuvant therapy. This study aims to explore the relationship between pre-treatment endoscopic tumour morphology and postoperative survival. Methods Patients with endoscopic descriptions of tumours were identified from the prospectively managed databases including the OCCAMS database. Tumours were classified as exophytic, ulcerating or stenosing. Kaplan Meier survival analysis and multivariable Cox regression analyses were performed to determine hazard ratios (HR) with 95% confidence intervals. Results 262 patients with oesophageal adenocarcinoma undergoing potentially curative resection were pooled from St Thomas’ Hospital (161) and the OCCAMS database (101). There were 70 ulcerating, 114 exophytic and 78 stenosing oesophageal adenocarcinomas. Initial tumour staging was similar across all groups (T3/4 tumours 71.4%, 70.2%, 74.4%). Median survival was 55 months, 51 months and 36 months respectively (p Conclusion This study demonstrates that endoscopic morphology may be an important pre-treatment prognostic factor in oesophageal cancer. Ulcerating, exophytic and stenosing tumours may represent different pathological processes and tumour biology.
TL;DR: The Holistic Approach to Unravelling Antibacterial Resistance in East Africa (HATUA) as mentioned in this paper is a multi-centre consortium that investigates the diverse drivers of drug-resistance in urinary tract infections (UTIs) in Tanzania, Uganda, Kenya and Tanzania.
Abstract: Introduction Antimicrobial resistance (AMR) is a global health threat that requires urgent research using a multidisciplinary approach. The biological drivers of AMR are well understood, but factors related to treatment-seeking and the social contexts of antibiotic (AB) use behaviours are less understood. Here we describe the Holistic Approach to Unravelling Antibacterial Resistance in East Africa (HATUA), a multi-centre consortium that investigates the diverse drivers of drug-resistance in urinary tract infections (UTIs) in East Africa. Methods and Analysis This study will take place in Uganda, Kenya and Tanzania. We will conduct geospatial mapping of AB sellers, and conduct mystery client studies and in-depth interviews (IDI) with drug sellers to investigate AB provision practices. In parallel, we will conduct IDIs with doctors, alongside community focus groups. Clinically diagnosed UTI patients will be recruited from healthcare centres, provide urine samples, and complete a questionnaire capturing retrospective treatment pathways, socio-demographic characteristics, attitudes and knowledge. Bacterial isolates from urine and stool samples will be subject to culture and antibiotic susceptibility testing (C&AST). Genomic DNA from bacterial isolates will be extracted with a subset being sequenced. A follow-up household interview will be conducted with 1800 UTI-positive patients, where further environmental samples will be collected. A sub-sample of patients will be interviewed using qualitative tools. Questionnaire data, microbiological analysis and qualitative data will be linked at the individual level. Quantitative data will be analysed using statistical modelling including Bayesian network analysis, and all forms of qualitative data analysed through iterative thematic content analysis. Ethics and Dissemination Approvals have been obtained from all national and local ethical review bodies in East Africa and the UK. Results will be disseminated in communities, with local and global policy stakeholders, and in academic circles. They will have great potential to inform policy, improve clinical practice and build regional pathogen surveillance capacity.