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PP13. CHERNOBYL, BREXIT AND BRAIN TUMOURS

PP13. CHERNOBYL, BREXIT AND BRAIN TUMOURS Abstracts lagen encoding genes (e.g. COL1A1, COL1A2, COL3A1, COL6A3) or their serves a catchment area of nearly 3.5 million, 1% (32,253) of whom are mutation (e.g. COL7A1), and enhanced ECM degradation via dysregulation recorded to have been born in Poland at the last 2011 census. Over the past of SAPK/JNK signaling. Mutational signature analysis revealed striking enrich- few years, we have observed a relatively large number of Polish-born UK ment of C to T transitions, accounting for 40 to 50% of all base-substitution residents presenting with primary brain and central nervous system (CNS) mutations, implicating CT transition enhancing mutagenic processes in the eti- tumours. Data collection is ongoing but we believe that the numbers of ology of GBM. Aberrant epigenetic regulation consistent with dysfunctional newly diagnosed cases far exceeds the published age standardized incidence polycomb-mediated gene repression manifests in inappropriate activation of rate for brain and CNS tumors in Poland which is 10 per 100,000. If a putative tumour promoter genes in recurrent tumours. Of 188 genes identi- higher than expected incidence of brain and CNS tumors in our local Pol- fied as differentially expressed in our GBM cohort, 38 genes were shared ish population is observed this could be explained by a number of soci- in a separate validation cohort of tumours from the TCGA GBM database. oeconomic/health factors. However, as we mark the 30th anniversary of This includes seven genes (ADM, HPCAL4, SNCB, SV2B, TMEM130, H19, the Chernobyl accident this year, we should also keep in mind geohistori- VSNL1) with correlations between gene expression and patient survival cal factors that may be relevant to this particular immigrant population. according to Kaplan-Meier plots generated from TCGA data. This study has Poland neighbours Ukraine where the Chernobyl accident occurred, and highlighted new insights into GBM tumour recurrence and revealed potential was affected by the radioactive fallout that followed the disaster. The main novel candidates as prognostic biomarkers and rational therapeutic targets. health impact from Chernobyl has so far been the increased incidence of thyroid cancer but there is now increasing concern about the increased risk of non-thyroid, solid tumors. An increased incidence in CNS tumours has PP12. NAVIGATING “HEALTHCARE LANDSCAPES:” THE MULTIPLE been seen in atomic bomb survivors where even a low exposures (<1Sv) was JOURNEYS OF PEOPLE WITH PRIMARY BRAIN TUMOURS associated with an increased risk. Cohort studies in Belarus and Ukraine, Mr Henry Llewellyn, Mr Lewis Thorne, Dr Elizabeth L Sampson, two countries with the most radiation contamination, have so far not Dr Elena Wilson, Ms Jane Baranowski, Prof Paul Higgs; University College demonstrated any significant increase in non-thyroid cancers but it may London still be early days. We know from long term follow up studies of child- hood cancers that radiation-induced brain and CNS tumors can present INTRODUCTION: Patients diagnosed with primary brain tumours are very later, 20, 30 years after initial exposure. Due to the very long half life thrown into a new and unfamiliar world. Here, they are involved in mak- (30 years) of the main radioisotope responsible for the contamination (Cae- ing complex decisions about care and treatment. Such decision-making sium-137), the nature of the exposure is extremely protracted. The World is often made difficult by fluctuating cognition and communication dif - Health Organisation recently issued a press release stating that “protracted ficulties. While clinical expertise and standardised patient pathways set exposure to low doses of ionizing radiation increases the risk of death from out the journey ahead, these themselves are underpinned by logics that solid cancers.” People at highest risk of developing solid cancers as a result might be unfamiliar or contrary to patients’ expectations and values. As of radiation exposure due to Chernobyl would be those who were chil- a consequence, patients’ approaches to decision-making as well as their dren at the time of the disaster or born just after 1986 when the accident resultant journeys greatly differ, even among patients with the same diag- occurred. We will present data showing a range of CNS tumours in our nosis. We take a social science perspective to examine how patients navi- Polish patients including information about geographical location and age gate illness and healthcare. METHOD: Using a qualitative ethnographic at the time of the Chernobyl nuclear accident as well as age of diagnosis of design over 18-months (Nov 2014-April 2016), we followed a group of brain tumour. In areas affected by rapidly changing patterns of immigration 16 patients with malignant and non-malignant primary brain tumours it is important to be aware of the oncological risk factors associated with through various points of their care journeys. During this, patients were the groups that we serve. interviewed regularly by HL who also observed and recorded their clinical appointments with oncologists, surgeons, neurologists, nurses and other healthcare professionals in detailed fieldnotes. Interview transcripts and PP14. NETWORK ANALYSIS REVEALS INSIGHTS INTO H3F3A fieldnotes were analysed thematically. RESULTS: Patients’ experiences of BIOLOGY IN PEDIATRIC GLIOBLASTOMA care and their approaches to decision-making differed significantly, even Dr Anbarasu Lourdusamy, Prof Richard Grundy; Children’s Brain Tumour among those with the same tumour subtype and grade. To make sense Research Centre, The University of Nottingham of these differences we introduce the concept of “healthcare landscapes.” Here, we define landscapes as “the imagined landscapes of care and treat - BACKGROUND: H3 histone, family 3A (H3F3A) encodes H3.3 histone ment in which patients find themselves and through which they must try protein monomers, which plays a central role in chromatin structure and to navigate.” We suggest that patients construct these as they interpret gene regulation. Recent studies have reported highly recurrent mutations clinical information, treatment, risk, uncertainty, evidence, credibility, best affecting the N-terminal tail of H3.3 and causing amino acid substitution practice, and the goals of care. Landscapes differ in terms of scale and the of lysine 27 to methionine (K27M) and of glycine 34 to arginine or valine features they include, for example, standard care pathways, clinical tri- (G34A or G34V) in pediatric glioblastoma (GBM), which in turns linked als or ideas about “medical tourism.” Extrapolating themes from patients’ to two subgroups with distinct clinical and pathological features. However, accounts, we suggest a typology of landscapes that can be categorised into effect of H3F3A mutations on other closely related genes is not yet fully “standard” and “beyond standard,” with the latter further subdivided into explored. Thus, we performed a network analysis to gain insights into the “private care,” “experimental,” “global,” “alternative” and “compound.” biology of H3F3A in pediatric GBM. METHODS: We constructed H3F3A We illustrate these types using case studies of specific patients. DISCUS - network by extracting gene products that directly interact with H3F3A SION: Our concept of “healthcare landscapes” offers an alternative way to from protein-protein interaction (PPI) databases. To examine the network view the patient experience, acknowledging the complexity of care and its wiring around H3F3A, we combined pediatric GBM gene expression data contingent and improvised nature. In addition, it allows room for patients’ from three independent studies and computed the correlation between interpretations and styles of decision-making and shows how, for many, H3F3A and all interacting genes for each mutation status (K27M or G34) standard care is but one in a range of possibilities. In this way, we suggest and H3F3A wild type (WT). We then identified network of differentially that the concept of “healthcare landscapes” disrupts the idea that care tra- co-expressed gene pairs that either gained or lost correlation in mutation jectories are linear and straightforward. CONCLUSION: Our concept of relative to the WT tumours. RESULTS: Through mining of PPI networks, “healthcare landscapes” helps to explain differences in care and treatment 106 gene products were identified to interact with H3F3A. Many of these even when diagnoses are the same. It is useful for clinicians by alerting genes were known to be involved in chromatin modification (47 genes; them to the ways in which patients interpret information and by providing FDR  =  2.17E-38), DNA metabolic process (34 genes; FDR  =  3.23E-16), a basic template in which to situate their patients’ approaches to decision- DNA repair (22 genes; FDR  =  8.18E-12), and histone methylation (13 making. It is useful to policy-makers by offering a new entry point into genes; FDR = 2.75E-11). H3F3A network was largely perturbed by K27M discussions about the equity of care, wherein we might distinguish between mutation than G34 (44 interactions changed in K27M and 24 in G34 when landscapes that are impoverished of features and slight in scale and those compared with WT, FDR < 0.05). Of these interactions, only four were that are rich and abundant. perturbed by both mutations: H3F3A - ASB9, H3F3A - CBX3, H3F3A - HIST2H2BE, and H3F3A - PDGFRA, suggesting distinct mechanisms by which H3F3A mutations might be inducing transcriptional program- ming in pediatric GBM. A relatively small number of H3F3A interactions were identified between IDH1 mutation and WT tumours from adult GBM Dr kazumi chia, Ms Rhiannon Davies, Dr Lucy Brazil; Guy’s and St. (7 interactions from K27M and 1 from G34) and in pediatric medullo- Thomas’ NHS Foundation Trust, King’s College Hospital blastomas (2 interactions from K27M and 1 from G34), demonstrating the robustness and specificity of identified interactions in pediatric GBM. Following the 2004 enlargement of the European Union, many hundreds CONCLUSION: In conclusion, the network analysis represents a new of thousands of people from the newly ascended states travelled to the approach for the prioritization of H3F3A interacting partners in pediatric UK to look for work. Polish workers were by far the largest group and GBM, providing new insights into network dependencies in pediatric GBM today, Polish is the second most commonly spoken language in the UK. In subgroups and potentially enabling the identification of new diagnostic central London, the multidisciplinary, neuro-oncology team at Guy’s and and therapeutic targets. St. Thomas’ NHS Foundation Trust (GSTFT) and Kings College Hospital i4 NEURO-ONCOLOGY • january 2017 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuro-Oncology Oxford University Press

PP13. CHERNOBYL, BREXIT AND BRAIN TUMOURS

chia, Dr kazumi; Davies, Ms Rhiannon; Brazil, Dr Lucy
Neuro-Oncology , Volume 19 (suppl_1) – Jan 1, 2017
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Oxford University Press
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© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
ISSN
1522-8517
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1523-5866
DOI
10.1093/neuonc/now293.012
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Abstract

Abstracts lagen encoding genes (e.g. COL1A1, COL1A2, COL3A1, COL6A3) or their serves a catchment area of nearly 3.5 million, 1% (32,253) of whom are mutation (e.g. COL7A1), and enhanced ECM degradation via dysregulation recorded to have been born in Poland at the last 2011 census. Over the past of SAPK/JNK signaling. Mutational signature analysis revealed striking enrich- few years, we have observed a relatively large number of Polish-born UK ment of C to T transitions, accounting for 40 to 50% of all base-substitution residents presenting with primary brain and central nervous system (CNS) mutations, implicating CT transition enhancing mutagenic processes in the eti- tumours. Data collection is ongoing but we believe that the numbers of ology of GBM. Aberrant epigenetic regulation consistent with dysfunctional newly diagnosed cases far exceeds the published age standardized incidence polycomb-mediated gene repression manifests in inappropriate activation of rate for brain and CNS tumors in Poland which is 10 per 100,000. If a putative tumour promoter genes in recurrent tumours. Of 188 genes identi- higher than expected incidence of brain and CNS tumors in our local Pol- fied as differentially expressed in our GBM cohort, 38 genes were shared ish population is observed this could be explained by a number of soci- in a separate validation cohort of tumours from the TCGA GBM database. oeconomic/health factors. However, as we mark the 30th anniversary of This includes seven genes (ADM, HPCAL4, SNCB, SV2B, TMEM130, H19, the Chernobyl accident this year, we should also keep in mind geohistori- VSNL1) with correlations between gene expression and patient survival cal factors that may be relevant to this particular immigrant population. according to Kaplan-Meier plots generated from TCGA data. This study has Poland neighbours Ukraine where the Chernobyl accident occurred, and highlighted new insights into GBM tumour recurrence and revealed potential was affected by the radioactive fallout that followed the disaster. The main novel candidates as prognostic biomarkers and rational therapeutic targets. health impact from Chernobyl has so far been the increased incidence of thyroid cancer but there is now increasing concern about the increased risk of non-thyroid, solid tumors. An increased incidence in CNS tumours has PP12. NAVIGATING “HEALTHCARE LANDSCAPES:” THE MULTIPLE been seen in atomic bomb survivors where even a low exposures (<1Sv) was JOURNEYS OF PEOPLE WITH PRIMARY BRAIN TUMOURS associated with an increased risk. Cohort studies in Belarus and Ukraine, Mr Henry Llewellyn, Mr Lewis Thorne, Dr Elizabeth L Sampson, two countries with the most radiation contamination, have so far not Dr Elena Wilson, Ms Jane Baranowski, Prof Paul Higgs; University College demonstrated any significant increase in non-thyroid cancers but it may London still be early days. We know from long term follow up studies of child- hood cancers that radiation-induced brain and CNS tumors can present INTRODUCTION: Patients diagnosed with primary brain tumours are very later, 20, 30 years after initial exposure. Due to the very long half life thrown into a new and unfamiliar world. Here, they are involved in mak- (30 years) of the main radioisotope responsible for the contamination (Cae- ing complex decisions about care and treatment. Such decision-making sium-137), the nature of the exposure is extremely protracted. The World is often made difficult by fluctuating cognition and communication dif - Health Organisation recently issued a press release stating that “protracted ficulties. While clinical expertise and standardised patient pathways set exposure to low doses of ionizing radiation increases the risk of death from out the journey ahead, these themselves are underpinned by logics that solid cancers.” People at highest risk of developing solid cancers as a result might be unfamiliar or contrary to patients’ expectations and values. As of radiation exposure due to Chernobyl would be those who were chil- a consequence, patients’ approaches to decision-making as well as their dren at the time of the disaster or born just after 1986 when the accident resultant journeys greatly differ, even among patients with the same diag- occurred. We will present data showing a range of CNS tumours in our nosis. We take a social science perspective to examine how patients navi- Polish patients including information about geographical location and age gate illness and healthcare. METHOD: Using a qualitative ethnographic at the time of the Chernobyl nuclear accident as well as age of diagnosis of design over 18-months (Nov 2014-April 2016), we followed a group of brain tumour. In areas affected by rapidly changing patterns of immigration 16 patients with malignant and non-malignant primary brain tumours it is important to be aware of the oncological risk factors associated with through various points of their care journeys. During this, patients were the groups that we serve. interviewed regularly by HL who also observed and recorded their clinical appointments with oncologists, surgeons, neurologists, nurses and other healthcare professionals in detailed fieldnotes. Interview transcripts and PP14. NETWORK ANALYSIS REVEALS INSIGHTS INTO H3F3A fieldnotes were analysed thematically. RESULTS: Patients’ experiences of BIOLOGY IN PEDIATRIC GLIOBLASTOMA care and their approaches to decision-making differed significantly, even Dr Anbarasu Lourdusamy, Prof Richard Grundy; Children’s Brain Tumour among those with the same tumour subtype and grade. To make sense Research Centre, The University of Nottingham of these differences we introduce the concept of “healthcare landscapes.” Here, we define landscapes as “the imagined landscapes of care and treat - BACKGROUND: H3 histone, family 3A (H3F3A) encodes H3.3 histone ment in which patients find themselves and through which they must try protein monomers, which plays a central role in chromatin structure and to navigate.” We suggest that patients construct these as they interpret gene regulation. Recent studies have reported highly recurrent mutations clinical information, treatment, risk, uncertainty, evidence, credibility, best affecting the N-terminal tail of H3.3 and causing amino acid substitution practice, and the goals of care. Landscapes differ in terms of scale and the of lysine 27 to methionine (K27M) and of glycine 34 to arginine or valine features they include, for example, standard care pathways, clinical tri- (G34A or G34V) in pediatric glioblastoma (GBM), which in turns linked als or ideas about “medical tourism.” Extrapolating themes from patients’ to two subgroups with distinct clinical and pathological features. However, accounts, we suggest a typology of landscapes that can be categorised into effect of H3F3A mutations on other closely related genes is not yet fully “standard” and “beyond standard,” with the latter further subdivided into explored. Thus, we performed a network analysis to gain insights into the “private care,” “experimental,” “global,” “alternative” and “compound.” biology of H3F3A in pediatric GBM. METHODS: We constructed H3F3A We illustrate these types using case studies of specific patients. DISCUS - network by extracting gene products that directly interact with H3F3A SION: Our concept of “healthcare landscapes” offers an alternative way to from protein-protein interaction (PPI) databases. To examine the network view the patient experience, acknowledging the complexity of care and its wiring around H3F3A, we combined pediatric GBM gene expression data contingent and improvised nature. In addition, it allows room for patients’ from three independent studies and computed the correlation between interpretations and styles of decision-making and shows how, for many, H3F3A and all interacting genes for each mutation status (K27M or G34) standard care is but one in a range of possibilities. In this way, we suggest and H3F3A wild type (WT). We then identified network of differentially that the concept of “healthcare landscapes” disrupts the idea that care tra- co-expressed gene pairs that either gained or lost correlation in mutation jectories are linear and straightforward. CONCLUSION: Our concept of relative to the WT tumours. RESULTS: Through mining of PPI networks, “healthcare landscapes” helps to explain differences in care and treatment 106 gene products were identified to interact with H3F3A. Many of these even when diagnoses are the same. It is useful for clinicians by alerting genes were known to be involved in chromatin modification (47 genes; them to the ways in which patients interpret information and by providing FDR  =  2.17E-38), DNA metabolic process (34 genes; FDR  =  3.23E-16), a basic template in which to situate their patients’ approaches to decision- DNA repair (22 genes; FDR  =  8.18E-12), and histone methylation (13 making. It is useful to policy-makers by offering a new entry point into genes; FDR = 2.75E-11). H3F3A network was largely perturbed by K27M discussions about the equity of care, wherein we might distinguish between mutation than G34 (44 interactions changed in K27M and 24 in G34 when landscapes that are impoverished of features and slight in scale and those compared with WT, FDR < 0.05). Of these interactions, only four were that are rich and abundant. perturbed by both mutations: H3F3A - ASB9, H3F3A - CBX3, H3F3A - HIST2H2BE, and H3F3A - PDGFRA, suggesting distinct mechanisms by which H3F3A mutations might be inducing transcriptional program- ming in pediatric GBM. A relatively small number of H3F3A interactions were identified between IDH1 mutation and WT tumours from adult GBM Dr kazumi chia, Ms Rhiannon Davies, Dr Lucy Brazil; Guy’s and St. (7 interactions from K27M and 1 from G34) and in pediatric medullo- Thomas’ NHS Foundation Trust, King’s College Hospital blastomas (2 interactions from K27M and 1 from G34), demonstrating the robustness and specificity of identified interactions in pediatric GBM. Following the 2004 enlargement of the European Union, many hundreds CONCLUSION: In conclusion, the network analysis represents a new of thousands of people from the newly ascended states travelled to the approach for the prioritization of H3F3A interacting partners in pediatric UK to look for work. Polish workers were by far the largest group and GBM, providing new insights into network dependencies in pediatric GBM today, Polish is the second most commonly spoken language in the UK. In subgroups and potentially enabling the identification of new diagnostic central London, the multidisciplinary, neuro-oncology team at Guy’s and and therapeutic targets. St. Thomas’ NHS Foundation Trust (GSTFT) and Kings College Hospital i4 NEURO-ONCOLOGY • january 2017

Journal

Neuro-Oncology – Oxford University Press

Published: Jan 1, 2017

There are no references for this article.