Author
Nigel B. Jamieson
Other affiliations: Royal North Shore Hospital, Johns Hopkins University, University of Glasgow ...read more
Bio: Nigel B. Jamieson is an academic researcher from Glasgow Royal Infirmary. The author has contributed to research in topics: Pancreatic cancer & Medicine. The author has an hindex of 44, co-authored 131 publications receiving 10913 citations. Previous affiliations of Nigel B. Jamieson include Royal North Shore Hospital & Johns Hopkins University.
Topics: Pancreatic cancer, Medicine, Stromal cell, Cancer, Transcriptome
Papers published on a yearly basis
Papers
More filters
University of Queensland1, University of Glasgow2, QIMR Berghofer Medical Research Institute3, Garvan Institute of Medical Research4, Baylor College of Medicine5, University of Utah6, University of Adelaide7, South Australia Pathology8, Harvard University9, Campbelltown Hospital10, St. Vincent's Health System11, University of New South Wales12, University of Newcastle13, Royal North Shore Hospital14, Royal Prince Alfred Hospital15, University of Sydney16, Fiona Stanley Hospital17, Royal Adelaide Hospital18, Princess Alexandra Hospital19, University of Western Australia20, Beatson West of Scotland Cancer Centre21, Southern General Hospital22, Dresden University of Technology23, University of Texas MD Anderson Cancer Center24, Memorial Sloan Kettering Cancer Center25, Johns Hopkins University School of Medicine26, University of Verona27, Mayo Clinic28, University of Melbourne29
TL;DR: Detailed genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing.
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
2,443 citations
QIMR Berghofer Medical Research Institute1, Garvan Institute of Medical Research2, University of Queensland3, Royal North Shore Hospital4, University of Western Sydney5, Fremantle Hospital6, Royal Adelaide Hospital7, Princess Alexandra Hospital8, University of Western Australia9, Glasgow Royal Infirmary10, Beatson West of Scotland Cancer Centre11, University of Bergen12, Dresden University of Technology13, Johns Hopkins University School of Medicine14, University of Texas MD Anderson Cancer Center15, Memorial Sloan Kettering Cancer Center16, University of Verona17, University of California, San Francisco18, University of Glasgow19
TL;DR: Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency, and 4 of 5 individuals with these measures of defective DNA maintenance responded to platinum therapy.
Abstract: Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
2,035 citations
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
TL;DR: In this paper, the authors used genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer.
Abstract: Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.
774 citations
QIMR Berghofer Medical Research Institute1, University of Queensland2, University of Glasgow3, Garvan Institute of Medical Research4, University of Padua5, Royal Brisbane and Women's Hospital6, Queensland University of Technology7, University of Newcastle8, Peking University9, Princess Alexandra Hospital10, St. Vincent's Health System11, Glasgow Royal Infirmary12, Human Genome Sequencing Center13, Baylor College of Medicine14, Children's Hospital at Westmead15, Children's Medical Research Institute16, Royal North Shore Hospital17, University of Sydney18, Royal Prince Alfred Hospital19, University of Western Sydney20, Fremantle Hospital21, Royal Adelaide Hospital22, University of Western Australia23, St John of God Subiaco Hospital24, University of Melbourne25
TL;DR: In this paper, the authors performed whole-genome sequencing of 102 primary pancreatic neuroendocrine tumours and defined the genomic events that characterize their pathogenesis, including a deficiency in G:C,>T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase.
Abstract: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
637 citations
Cited by
More filters
Institute for Systems Biology1, BC Cancer Agency2, University of California, San Francisco3, University of North Carolina at Chapel Hill4, Columbia University5, Discovery Institute6, Massachusetts Institute of Technology7, Arizona State University8, Sage Bionetworks9, Harvard University10, Johns Hopkins University11, Stanford University12, University of Calgary13, Université libre de Bruxelles14, University of Texas MD Anderson Cancer Center15, Medical College of Wisconsin16, Qatar Airways17, Cold Spring Harbor Laboratory18, University of São Paulo19, Henry Ford Hospital20, University of Alabama at Birmingham21, Van Andel Institute22, Stony Brook University23
TL;DR: An extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA identifies six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis.
3,246 citations
University of California, San Francisco1, Cold Spring Harbor Laboratory2, Icahn School of Medicine at Mount Sinai3, Oregon Health & Science University4, Wistar Institute5, University of Maryland, Baltimore County6, Huntsman Cancer Institute7, La Jolla Institute for Allergy and Immunology8, University of Pennsylvania9, Harvard University10, University of Michigan11, Massachusetts Institute of Technology12
TL;DR: By parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
Abstract: The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
2,920 citations
University of Queensland1, University of Glasgow2, QIMR Berghofer Medical Research Institute3, Garvan Institute of Medical Research4, Baylor College of Medicine5, University of Utah6, South Australia Pathology7, University of Adelaide8, Harvard University9, Campbelltown Hospital10, St. Vincent's Health System11, University of New South Wales12, University of Newcastle13, Royal North Shore Hospital14, University of Sydney15, Royal Prince Alfred Hospital16, Fiona Stanley Hospital17, Royal Adelaide Hospital18, Princess Alexandra Hospital19, University of Western Australia20, Beatson West of Scotland Cancer Centre21, Southern General Hospital22, Dresden University of Technology23, University of Texas MD Anderson Cancer Center24, Memorial Sloan Kettering Cancer Center25, Johns Hopkins University School of Medicine26, University of Verona27, Mayo Clinic28, University of Melbourne29
TL;DR: Detailed genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing.
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
2,443 citations
Harvard University1, Erasmus University Rotterdam2, University of Pennsylvania3, Laval University4, University of Ulsan5, University of California, San Francisco6, Yale University7, Radboud University Nijmegen8, University of Southern California9, Merck & Co.10, Memorial Sloan Kettering Cancer Center11
TL;DR: Pembrolizumab was associated with significantly longer overall survival and with a lower rate of treatment‐related adverse events than chemotherapy as second‐line therapy for platinum‐refractory advanced urothelial carcinoma.
Abstract: BackgroundPatients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. MethodsIn this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1–expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. ResultsThe median overall survival in the total population was 10.3 months (95% confidence interval [C...
2,362 citations
TL;DR: Analysis of advanced cancer patients treated with immune-checkpoint inhibitors shows that tumor mutational burden, as assessed by targeted next-generation sequencing, predicts survival after immunotherapy across multiple cancer types.
Abstract: Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.
2,343 citations