Showing papers by "Lorraine A. Chantrill published in 2017"
University of Queensland1, QIMR Berghofer Medical Research Institute2, 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, 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
Garvan Institute of Medical Research1, University of New South Wales2, Victor Chang Cardiac Research Institute3, St. Vincent's Health System4, Illawarra Health & Medical Research Institute5, University of Sydney6, Royal Prince Alfred Hospital7, Royal North Shore Hospital8, University of Glasgow9, Glasgow Royal Infirmary10, University of California, San Diego11, University of South Australia12
TL;DR: A graded response to priming is demonstrated in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.
Abstract: The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or “priming,” using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Forster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.
209 citations
Garvan Institute of Medical Research1, QIMR Berghofer Medical Research Institute2, University of Queensland3, University of Glasgow4, University of New South Wales5, University of Adelaide6, Campbelltown Hospital7, St. Vincent's Health System8, University of Newcastle9, Royal North Shore Hospital10, University of Sydney11, Royal Prince Alfred Hospital12, Fiona Stanley Hospital13, Royal Adelaide Hospital14, Princess Alexandra Hospital15, University of Western Australia16, Glasgow Royal Infirmary17, Beatson West of Scotland Cancer Centre18, Southern General Hospital19, Johns Hopkins University School of Medicine20, University of Verona21, University of California, San Francisco22, University of Erlangen-Nuremberg23, University of Melbourne24
TL;DR: Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
171 citations
Garvan Institute of Medical Research1, University of Sydney2, University of New South Wales3, Royal Prince Alfred Hospital4, QIMR Berghofer Medical Research Institute5, Royal North Shore Hospital6, Boston Children's Hospital7, Illumina8, University of Melbourne9, University of Western Australia10, Kolling Institute of Medical Research11
TL;DR: Using the work of the Australian Pancreatic Cancer Genome Initiative, barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research are discussed that may be useful for others developing their own policies.
Abstract: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium–high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.
79 citations
TL;DR: This corrects the article to show that the method used to derive the H2O2 “spatially aggregating force” is based on a two-step process, not a single step, like in the previous version of this paper.
Abstract: Nature 543, 65–71 (2017); doi:10.1038/nature21063 It has been brought to our attention that in Fig. 2d of this Article, an incorrect Sanger trace was used to represent the breakpoint of the EWSR1 and FLI1 type 2 fusion. This was due to an error during manuscript preparation, when we inadvertently inserted the electrophoretic trace referring to EWSR1 splicing variants.
10 citations
TL;DR: A follow up analysis of the screened cohort provides insight into the clinical utilisation of targetable molecular results in pancreas cancer.
Abstract: 314Background: The IMPaCT trial screened patients with advanced pancreas cancer for molecular targets and aimed to test molecularly guided therapy in a pilot randomized study, but closed in December 2015 having delivered personalized treatment to only 1 patient. A follow up analysis of the screened cohort provides insight into the clinical utilisation of targetable molecular results in pancreas cancer. Methods: IMPaCT screened for 3 genetic phenotypes matched to precision treatment: Her2 amplification (trastuzamab + gemcitabine), KRAS wildtype (erlotinib + gemcitabine) and DNA damage repair pathway defects (platinum-based). Previously recruited primary resected APGI participants known to be alive were also screened for these targets. The initial pilot protocol included randomisation, but after amendment in early 2015, became a single-arm study allowing one cycle of gemcitabine + nab-paclitaxel during screening. Results: A total of 101 potential patients were screened. This was enriched for patients with k...
1 citations
Alfred Hospital1, University of Sydney2, University of New South Wales3, University of Melbourne4, Hebron University5, Campbelltown Hospital6, Garvan Institute of Medical Research7, Royal North Shore Hospital8, Royal Hobart Hospital9, Imperial College Healthcare10, Seconda Università degli Studi di Napoli11, Princess Alexandra Hospital12, Flinders University13, University of Adelaide14
1 citations