Author
Lorraine A. Chantrill
Other affiliations: Garvan Institute of Medical Research, University of New South Wales, Campbelltown Hospital ...read more
Bio: Lorraine A. Chantrill is an academic researcher from Wollongong Hospital. The author has contributed to research in topics: Pancreatic cancer & Irinotecan. The author has an hindex of 22, co-authored 51 publications receiving 7940 citations. Previous affiliations of Lorraine A. Chantrill include Garvan Institute of Medical Research & University of New South Wales.
Topics: Pancreatic cancer, Irinotecan, Medicine, KRAS, Cancer
Papers
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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
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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
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University of New South Wales1, Garvan Institute of Medical Research2, Bankstown Lidcombe Hospital3, University of Queensland4, Baylor College of Medicine5, Ontario Institute for Cancer Research6, University of Newcastle7, University of Sydney8, Royal North Shore Hospital9, Life Technologies10, St. Vincent's Health System11, Royal Prince Alfred Hospital12, Fremantle Hospital13, Royal Adelaide Hospital14, University of Western Australia15, University of California, Los Angeles16, University Health Network17, Mayo Clinic18, University of Toronto19, Johns Hopkins University20, University of Verona21, University of California, San Francisco22, Houston Methodist Hospital23, Cancer Research UK24, Wellcome Trust Sanger Institute25, University of Minnesota26, Netherlands Cancer Institute27
TL;DR: It is found that frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, are also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement ofAxon guidance genes in pancreatic carcinogenesis.
Abstract: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
1,752 citations
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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
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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, Baylor College of Medicine13, Human Genome Sequencing Center14, Children's Hospital at Westmead15, Children's Medical Research Institute16, University of Sydney17, Royal North Shore Hospital18, Royal Prince Alfred Hospital19, University of Western Sydney20, Fremantle Hospital21, Royal Adelaide Hospital22, St John of God Subiaco Hospital23, University of Western Australia24, 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
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TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
Abstract: Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.
6,441 citations
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TL;DR: The Reactome Knowledgebase provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations—an extended version of a classic metabolic map, in a single consistent data model.
Abstract: The Reactome Knowledgebase (www.reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression pattern surveys or somatic mutation catalogues from tumour cells. Over the last two years we redeveloped major components of the Reactome web interface to improve usability, responsiveness and data visualization. A new pathway diagram viewer provides a faster, clearer interface and smooth zooming from the entire reaction network to the details of individual reactions. Tool performance for analysis of user datasets has been substantially improved, now generating detailed results for genome-wide expression datasets within seconds. The analysis module can now be accessed through a RESTFul interface, facilitating its inclusion in third party applications. A new overview module allows the visualization of analysis results on a genome-wide Reactome pathway hierarchy using a single screen page. The search interface now provides auto-completion as well as a faceted search to narrow result lists efficiently.
5,065 citations
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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
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2,777 citations
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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, 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